Novel compounds

ABSTRACT

Compounds of formula (I) defined herein exhibit human neutrophil elastase inhibitory properties and are useful for the treatment of disease or conditions in which HNE is implicated

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to European Patent Application No.16172196.4, filed on May 31, 2016, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to imidazolone derivatives having exhibithuman neutrophil elastase inhibitory properties, and the therapeutic useof such a derivative.

Discussion of the Background

Human neutrophil elastase (HNE) is a 32 kDa serine proteinase found inthe azurophilic granules of neutrophils. It has a role in thedegradation of a wide range of extracellular matrix proteins, includingfibronectin, laminin, proteoglycans, Type III and Type IV collagens aswell as elastin (see Bieth, G. in Regulation of Matrix accumulation,Mecham, R. P. (Eds), Academic Press, NY, USA 1986, 217-306, which isincorporated herein by reference in its entirety). HNE has long beenconsidered to play an important role in homeostasis through repair anddisposal of damaged tissues via degradation of the tissue structuralproteins. It is also relevant in the defense against bacterial invasionby means of degradation of the bacterial body. In addition to itseffects on matrix tissues, FINE has been implicated in the upregulationof IL-8 gene expression and also induces IL-8 release from theepithelial cells of the lung. In animal models of Chronic ObstructivePulmonary Disease induced by tobacco smoke exposure both small moleculeinhibitors and protein inhibitors of HNE inhibit the inflammatoryresponse and the development of emphysema (see Wright, J. L. et al. Am.J Respir. Crit. Care Med. 2002, 166, 954-960; Churg, A. et al. Am. JRespir. Crit. Care Med. 2003, 168, 199-207, which are incorporatedherein by reference in their entireties). Thus, HNE may play a role bothin matrix destruction and in amplifying inflammatory responses inchronic respiratory diseases where neutrophil influx is a characteristicfeature. Indeed, FINE is believed to play a role in several pulmonarydiseases, including chronic obstructive pulmonary disease (COPD), cysticfibrosis (CF), acute respiratory distress syndrome (ARDS), pulmonaryemphysema, pneumonia and lung fibrosis. It is also implicated in severalcardiovascular diseases in which tissue remodeling is involved, forexample, in heart failure and the generation of ischemic tissue injuryfollowing acute myocardial infarction.

COPD is an umbrella term encompassing three different pathologicalconditions, all of which contribute to limitation of airflow: chronicbronchitis, emphysema and small-airway disease. Generally all three willexist to varying extents in patients presenting with COPD, and all threemay be due to neutrophil-mediated inflammation, as supported by theincreased number of neutrophils observed in bronchoalveolar leakage(BAL) fluids of COPD patients (see Thompson, A. B.; Daughton, D.; et al.Am. Rev. Respir. Dis. 1989, 140, 1527-1537, which is incorporated hereinby reference in its entierty). The major pathogenic determinant in COPDhas long been considered to be the protease-anti-protease balance (alsoknown as the “elastase:anti-elastase hypothesis”), in which an imbalanceof FINE and endogenous antiproteases such as α1-antitrypsin (α₁-AT),secretory leukocyte protease inhibitor (SLPI) and pre-elafin leads tothe various inflammatory disorders of COPD. Individuals that have agenetic deficiency of the protease inhibitor al-antitrypsin developemphysema that increases in severity over time (see Laurrell, C. B.;Erikkson, S Scand. J. Clin. Invest. 1963 15, 132-140, which isincorporated herein by reference in its entirety). An excess of HNE istherefore destructive, leading to the breakdown of pulmonary morphologywith loss of elasticity and destruction of alveolar attachments ofairways in the lung (emphysema) whilst simultaneously increasingmicrovascular permeability and mucus hypersecretion (chronicbronchitis).

Several human neutrophil inhibitors have been disclosed so far. Inparticular, WO2011/110858, WO2011/110859, WO 2014/095700, and WO2015/091281, which are incorporated herein by reference in theirentireties, describe pyrimidine derivatives having human neutrophilelastase inhibitory properties.

Although several HNE inhibitors have been disclosed so far as abovereported, there is still a need for further HNE inhibitors.Particularly, there is still a need for further HNE inhibitors endowedwith a high potency for FINE enzyme inhibition. Particularlyadvantageous would also be the identification of further FINE inhibitorsendowed with a high potency for HNE enzyme inhibition and which wouldshow an appropriate developability profile as an inhalation treatment.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelimidazolone derivatives having exhibit human neutrophil elastaseinhibitory properties.

It is another object of the present invention to provide novel methodsof treating and/or preventing certain diseases by administering such animidazolone derivative.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discovery ofthe compounds of formula (I) described below.

Thus, in one aspect, the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof:

wherein

A is selected from the group consisting of

X is selected from the group consisting of

or is selected from the group consisting of

R₁ is selected from the group consisting of

n is an integer from 1 to 4;

m is 0 or an integer from 1 to 4;

t is 0 or an integer from 1 to 4;

y is an integer from 1 to 4;

w is an integer from 1 to 4;

z is 0 or 1;

l is 0 or 1;

R₂ is —H or linear or branched —(C₁-C₄)alkyl;

R₃ is linear or branched —(C₁-C₄)alkyl or R₂ and R₃ may form together acycloalkyl;

R₄ is selected from the group consisting of-arylene-(C₁-C₄)alkylene-NR_(d)R_(e),-arylene-(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),-heteroarylene-(C₁-C₄)alkylene-NR_(d)R_(e),-heteroarylene-(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c) and heteroaryl, whereinany of such arylene-(C₁-C₄)alkylene-NR_(d)R_(e),-arylene-(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),-heteroarylene-(C₁-C₄)alkylene-NR_(d)R_(e),-heteroarylene-(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c) and heteroaryl may beoptionally substituted by one or more —(C₁-C₄)alkyl or R₄ is selectedfrom the group consisting of

R₅ is selected from the group consisting of aryl-(C₁-C₄)alkylenoxy-,linear or branched (C₁-C₄)alkyl-OC(O)—NH—, —(CH₂)_(t)—NR_(d)R_(e),—(CH₂)—N⁺R_(a)R_(b)R_(c), —C(O)—N(R₁₀)(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)N(R₁₀)(C₁-C₄)alkyl ene-N⁺R_(a)R_(b)R_(c),—C(O)O(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)O(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),—(CH₂)NHC(O)—(C₁-C₄)alkylene-NR_(d)R_(e),—(CH₂)NHC(O)—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c), or is selected from agroup consisting of

R₆ is selected from the group consisting of —H, —(C₁-C₄)alkyl,aryl-(C₁-C₄)alkylene-OCO—, CF₃C(O)—, aryl-(C₁-C₄)alkylene, linear orbranched (C₁-C₄)alkyl-OC(O)—, —C(O)—(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),—C(O)O—(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)O—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),—C(O)—N(R₁₀)(C₁-C₄)alkylene-NR_(d)R_(e), —C(O)N(R₁₀)(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c);

R_(a) is —(C₁-C₄)alkyl;

R_(b) is —(C₁-C₄)alkyl;

R_(c) is selected from —(C₁-C₄)alkyl, aryl-(C₁-C₄)alkylene andheteroaryl-(C₁-C₄)alkylene, wherein said heteroaryl-(C₁-C₄)alkylene maybe optionally substituted by one or more —(C₁-C₄)alkyl groups;

R_(d) is —H or —(C₁-C₄)alkyl;

R_(e) is —H or —(C₁-C₄)alkyl;

R₇ is —H or —(C₁-C₄)alkyl;

R₈ is —H or —(C₁-C₄)alkyl;

R₉ is selected from the group consisting of heterocycloalkyl,heterocycloalkyl-(C₁-C₄)alkylene-, (C₁-C₄)alkylene-NR_(d)R_(e) and(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c);

R₁₀ is —H or —(C₁-C₄)alkyl;

wherein any of such heterocycloalkyl, aryl, heteroaryl andaryl-(C₁-C₄)alkylene may be optionally substituted by one or more groupsindependently selected from (C₁-C₄)alkyl and OR₇ and wherein thenitrogen atom in the heterocycloalkyl and heteroaryl groups may bequaternized.

The compounds of formula (I) can be prepared in the form of salts,particularly pharmaceutically acceptable salts, N-oxides, hydrates,solvates and polymorphs thereof. Any reference to a compound herein, orreference to “compounds of the invention”, “compounds of formula (I)”,and the like includes such compounds whether or not in salt, N-oxide,hydrate, solvate or polymorphic form.

The compounds of the present invention can be used in the treatment orprevention of diseases in which HNE is implicated, for example chronicobstructive pulmonary disease (COPD), bronchiectasis, chronicbronchitis, lung fibrosis, pneumonia, acute respiratory distresssyndrome (ARDS), pulmonary emphysema, smoking-induced emphysema andcystic fibrosis.

Hence other aspects of the invention are (i) a pharmaceuticalcomposition comprising a compound of the invention and apharmaceutically acceptable carrier or excipient; and (ii) the use of acompound of the invention for the manufacture of a medicament for thetreatment or prevention of a disease or condition in which HNE isimplicated.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Terminology

The term “(C_(a)-C_(b))alkyl” wherein a and b are integers refers to astraight or branched chain alkyl radical having from a to b carbonatoms. Thus when a is 1 and b is 6, for example, the term includesmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,t-butyl, n-pentyl and n-hexyl.

The term “(C_(a)-C_(b)) cycloalkyl”, wherein a and b are integers,refers to saturated monocyclic, bicyclic or tricyclic hydrocarbon groupscontaining from a to b ring carbon atoms, as appropriate. Examplesinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and adamantyl.

The term “heterocyclic” relates to a saturated mono-, bi- or tri-cyclicnon-aromatic radical containing one or more heteroatoms selected from S,N and O. In the case of bicyclic heterocyclic systems, included withinthe scope of the term are fused, spiro and bridged bicyclic systems,such as for example a quinuclidine ring. In particular, the term“C_(a)-C_(b)heterocycloalkyl” refers to monocyclic(C_(a)-C_(b))cycloalkyl groups, in which at least one ring carbon atomis replaced by a heteroatom (e.g. N, NH, S or O). Examples of(C_(a)-C_(b))heterocycloalkyl include pyrrolidinyl, thiazolidinyl,piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl.

By analogy, the expression “heterocycloalkylene” refers to a divalentheterocyclic radical as above defined. In particular, the expression“(C_(a)-C_(b))heterocycloalkylene” refers to a divalent(C_(a)-C_(b))heterocycloalkyl radical (such as for examplepyrrolidinene) wherein “(C_(a)-C_(b))heterocycloalkyl group is as abovedefined.

The expression “heteroaryl” refers to mono or bi-cyclic ring systemswith 5 to 11 ring atoms, in which at least one ring is aromatic and inwhich at least one ring atom is a heteroatom (e.g. N, NH, S or O).

Examples of suitable 5,6-membered heteroaryl monocyclic systems include,for instance thiophene (thiophenyl), pyrrole (pyrrolyl), pyrazole(pyrazolyl), imidazole (imidazolyl), isoxazole (isoxazolyl), oxazole(oxazolyl), isothiazole (isothiazolyl), thiazole (thiazolyl), pyridine(pyridinyl), pyrimidine (pyrimidinyl), pyridazine (pyridazinyl), andfuran (furanyl) radicals and the like.

Examples of suitable bi-cyclic heteroaryl ring systems includequinolones (quinolonyl), isoquinolines (isoquinolinyl), indole(indolyl), isoindole (isoindolyl), indolizine (indolizinyl),benzimidazole (benzimidazolyl), azabenzimidazole (azabenzimidazolyl),benzoxazole (benzoxazolyl), and benzothiazole (benzothiazolyl) radicalsand the like.

Throughout the specification the use of an asterisk “*” and “#” in thedefinition of a structural formula, indicates the points of attachmentfor the radical groups to the rest of the molecule. In particular, thenitrogen atom indicated with * in group A is directly linked to thecarbon atom of fragment

also indicated with *, and the carbon atom indicated with # in group Ais directly linked to the carbon atom of fragment

also indicated with #.

The term “pharmaceutically acceptable salts” refers to derivatives ofcompounds of formula (I) wherein the parent compound is modified byconverting any of the free acid or basic group, if present, into thecorresponding addition salt with any base or acid conventionallyintended as being pharmaceutically acceptable.

Where the compounds of the invention have at least one stereogeniccenter, they can exist as enantiomers. When the compounds according tothe invention possess two or more stereogenic centers, they canadditionally exist as diastereoisomers. It is to be understood that allsuch isomers and mixtures thereof in any proportion are encompassedwithin the scope of the present invention.

It is to be understood that all preferred groups or embodimentsdescribed here below for compounds of formula (I) may be combined amongeach other mutatis mutandis.

In one embodiment for compounds of formula (I), A is

In another embodiment, X is selected from the group consisting of

wherein n is 1, 2 or 3, m is 0, 1 or 2, z is 0 or 1, l is 0 or 1, y is 1or 2, w is 1 or 2.

In another embodiment, X is selected from the group consisting of

In another embodiment, R₁ is selected from the group consisting of

n is 1, 2 or 3; m is 0, 1 or 2.

In another embodiment, R₂ is —H or linear or branched —(C₁-C₄)alkyl.

In another embodiment, R₃ is linear or branched —(C₁-C₄)alkyl or R₂ andR₃ may form together a cycloalkyl.

In another embodiment, R₄ is selected from the group consisting of-arylene-(C₁-C₄)alkylene-NR_(d)R_(e),-arylene-(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),-heteroarylene-(C₁-C₄)alkylene-NR_(d)R_(e),-heteroarylene-(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c) and heteroaryl or isselected from the group consisting of

In another embodiment, R₅ is selected from the group consisting ofaryl-(C₁-C₄)alkylenoxy-, linear or branched (C₁-C₄)alkyl-OC(O)—NH—,—(CH₂)_(t)—NR_(d)R_(e), —(CH₂)_(t)—N⁺R_(a)R_(b)R_(c),—C(O)—N(R₁₀)(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)N(R₁₀)(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),—C(O)O(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)O(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),—(CH₂)NHC(O)—(C₁-C₄)alkylene-NR_(d)R_(e),—(CH₂)NHC(O)—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c), or is selected from agroup consisting of

In another embodiment, R₆ is selected from the group consisting of —H,—(C₁-C₄)alkyl, aryl-(C₁-C₄)alkylene-OCO—, CF₃C(O)—,aryl-(C₁-C₄)alkylene, linear or branched (C₁-C₄)alkyl-OC(O)—,—C(O)—(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),—C(O)O—(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)O—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),—C(O)—N(R₁₀)(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)N(R₁₀)(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c).

In another embodiment, R_(a) and R_(b) are independently —(C₁-C₄)alkyl,R_(c) is selected from —(C₁-C₄)alkyl, aryl-(C₁-C₄)alkylene andheteroaryl-(C₁-C₄)alkylene, wherein said heteroaryl-(C₁-C₄)alkylene maybe optionally substituted by one or more —(C₁-C₄)alkyl groups.

In another embodiment, R_(d) and R_(e) are independently —H or—(C₁-C₄)alkyl.

In another embodiment, R₇ and R₈ are independently —H or —(C₁-C₄)alkyl;R₉ is selected from the group consisting of heterocycloalkyl,heterocycloalkyl-(C₁-C₄)alkylene-, (C₁-C₄)alkylene-NR_(d)R_(e), and(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c); R₁₀ is —H or —(C₁-C₄)alkyl.

In another embodiment, any heterocycloalkyl, aryl, heteroaryl andaryl-(C₁-C₄)alkylene may be optionally substituted by one or more groupsindependently selected from (C₁-C₄)alkyl and OR₇ and wherein thenitrogen atom in the heterocycloalkyl and heteroaryl groups may bequaternized.

In another embodiment, A is

X is

n is 2 or 3; m is 0 or 2; R₇ is —H; R₅ is selected fromaryl-(C₁-C₄)alkylenoxy-, linear or branched (C₁-C₄)alkyl-OC(O)—NH,C(O)O(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),—(CH₂)NHC(O)—(C₁-C₄)alkylene-NR_(d)R_(e),—(CH₂)NHC(O)—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c) and—C(O)N(R₁₀)(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c)—wherein t is 0 or 1, R_(a)and R_(b) are independently —(C₁-C₄)alkyl, R_(c) is selected from—(C₁-C₄)alkyl, heteroaryl-(C₁-C₄)alkylene and aryl-(C₁-C₄)alkylene,R_(d) and R_(e) are independently —(C₁-C₄)alkyl, R₁₀ is —H or—(C₁-C₄)alkyl.

In another embodiment, A is

X is

n is 1 or 2; m is 1 or 2; R₇ is —H; R₅ is selected from—(CH₂)_(t)—NR_(d)R_(e), —(CH₂)_(t)—N⁺R_(a)R_(b)R_(c) wherein t is 0 or1, R_(a) and R_(b) are independently —(C₁-C₄)alkyl, R_(c) is selectedfrom —(C₁-C₄)alkyl, heteroaryl-(C₁-C₄)alkylene and aryl-(C₁-C₄)alkylene.

In another embodiment, A is

X is

n is 2; m is 2; R₇ is —H; R₅ is

R_(a) is —(C₁-C₄)alkyl; R_(b) is —(C₁-C₄)alkyl; R₁₀ is —H or—(C₁-C₄)alkyl.

In another embodiment, A is

X is

n is 2; m is 2; R₇ is —H; R₅ is

R_(a), R_(b) and R_(c) are independently —(C₁-C₄)alkyl.

In another embodiment, A is

X is

n is 2; m is 2; R₇ is —H or —(C₁-C₄)alkyl; R₆ is selected fromaryl-(C₁-C₄)alkylenoxy-,aryl-(C₁-C₄)alkylene-OCO—, CF₃C(O)—,—C(O)—(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)O—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),—C(O)N(R₁₀)(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c), and—C(O)—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c) wherein R_(d) is —H or—(C₁-C₄)alkyl; R_(e) is —H or —(C₁-C₄)alkyl, R_(a) is —(C₁-C₄)alkyl;R_(b) is —(C₁-C₄)alkyl; R_(c) is selected from —(C₁-C₄)alkyl; R₁₀ is —Hor —(C₁-C₄)alkyl.

In another embodiment, A is

X is

n is 1 or 2; m is 2; R₇ is —H or —(C₁-C₄)alkyl; R_(a) and R_(b) areindependently —(C₁-C₄)alkyl.

In another embodiment, A is

X is

R₂ is —H or linear or branched —(C₁-C₄)alkyl and R₃ is linear orbranched —(C₁-C₄)alkyl; R₄ is

wherein R₆ is —(C₁-C₄)alkyl.

In another embodiment, A is

X is

R₂ is —H or linear or branched —(C₁-C₄)alkyl and R₃ is linear orbranched —(C₁-C₄)alkyl; R₄ is

wherein R_(b) is —(C₁-C₄)alkyl and R_(c) is selected from —(C₁-C₄)alkyland aryl-(C₁-C₄)alkylene.

In another embodiment, A is

X is

z is 0 or 1; 1 is 0 or 1; R₆ is aryl-(C₁-C₄)alkylene optionallysubstituted by one or more OR₇, wherein R₇ is —(C₁-C₄)alkyl or R₆ islinear or branched (C₁-C₄)alkyl-OC(O)—.

In another embodiment, A is

X is

R₂ is —H and R₃ is linear or branched —(C₁-C₄)alkyl; R₁ is

n is 1 or 2; m is 2; R_(a) and R_(b) are independently —(C₁-C₄)alkyl; R₇is —H.

In another embodiment, A is

X is

R_(a) and R_(b) are independently 13 (C₁-C₄)alkyl; R₇ is —H.

In another embodiment, A is

X is

z is 0 or 1; 1 is 0 or 1; R_(a) and R_(b) are independently—(C₁-C₄)alkyl.

In another embodiment, A is

X is

R₂ is —H or linear or branched —(C₁-C₄)alkyl, R₃ is linear or branched—(C₁-C₄)alkyl or R₂ and R₃ may form together a cycloalkyl; R₄ isheteroaryl optionally substituted by (C₁-C₄)alkyl or R₄ is selected from-heteroarylene-(C₁-C₄)alkylene-NR_(d)R_(e) and-heteroarylene-(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c), wherein R_(a) is—(C₁-C₄)alkyl; R_(b) is —(C₁-C₄)alkyl; R_(c) is selected from—(C₁-C₄)alkyl, R_(d) is —H or —(C₁-C₄)alkyl; R_(e) is —H or—(C₁-C₄)alkyl.

In another embodiment, A is

X is

R_(a) and R_(b) are independently —(C₁-C₄)alkyl, n is 2, m is 2, y is 1or 2 and w is 1 or 2.

In another embodiment, A is

X is

R₂ is —H and R₃ is linear or branched —(C₁-C₄)alkyl; R₄ is

R₈ is —H or —(C₁-C₄)alkyl; R₉ is selected from -heterocycloalkyl andheterocycloalkyl-(C₁-C₄)alkylene-, wherein the heterocycloalkyl and theheterocycloalkyl-(C₁-C₄)alkylene- may optionally substituted by one ormore (C₁-C₄)alkyl and wherein the nitrogen atom in the heterocycloalkylgroup may be quaternized or R₉ is selected from—(C₁-C₄)alkylene-NR_(d)R_(e) and —(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),wherein R_(a) is —(C₁-C₄)alkyl; R_(b) is —(C₁-C₄)alkyl; R_(c) is—(C₁-C₄)alkyl, R_(d) is —H or —(C₁-C₄)alkyl; R_(e) is —H or—(C₁-C₄)alkyl.

In another embodiment, A is

X is

R₂ is —H and R₃ is linear or branched —(C₁-C₄)alkyl; R₄ is-arylene-(C₁-C₄)alkylene-NR_(d)R_(e), wherein R_(d) is —H or—(C₁-C₄)alkyl; R_(e) is —H or —(C₁-C₄)alkyl or R₄ is-arylene-(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c), wherein R_(a) is—(C₁-C₄)alkyl; R_(b) is —(C₁-C₄)alkyl; R_(c) is —(C₁-C₄)alkyl.

In another embodiment, A is

X is

R₂ is —H and R₃ is linear or branched —(C₁-C₄)alkyl; R₄ is

wherein R_(a) is —(C₁-C₄)alkyl; R_(b) is —(C₁-C₄)alkyl.

In another embodiment, A is

X is

R₂ is —H and R₃ is linear or branched —(C₁-C₄)alkyl; R₄ is

wherein R_(a) is —(C₁-C₄)alkyl; R_(b) is —(C₁-C₄)alkyl; R_(c) isselected from —(C₁-C₄)alkyl and aryl-(C₁-C₄)alkylene.

In another embodiment, A is

X is

n is 2; m is 2; R₇ is —H; R₅ is —(CH₂)_(t)—N⁺R_(a)R_(b)R_(c), wherein tis 1, R_(a) and R_(b) are independently —(C₁-C₄)alkyl, R_(c) isaryl-(C₁-C₄)alkylene.

In another embodiment, A is

X is

n is 2; m is 2; R₇ is —H, R₆ is selected from—C(O)—(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c), wherein R_(d) is —(C₁-C₄)alkyl;R_(e) is (C₁-C₄)alkyl, R_(a) is —(C₁-C₄)alkyl; R_(b) is —(C₁-C₄)alkyl;R_(c) is selected from —(C₁-C₄)alkyl.

In another embodiment, X is selected from the group consisting of

or is selected from the group consisting of

In another embodiment, a compound of the invention is selected in thegroup consisting of

Example Chemical name 15-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acidtrans-(4- dimethylaminomethyl-cyclohexyl)-amide 25-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid((1S,2S)- 2-benzyloxy-cyclopentyl)-amide 34-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidine-1-carboxylic acid benzyl ester 45-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid[1-(2,2,2- trifluoro-acetyl)-piperidin-4-yl]-amide 55-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid ((S)-1-pyridin-4-yl-ethyl)-amide 65-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid ((R)-1-pyridin-4-yl-ethyl)-amide 75-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid [3-(4-methoxy-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-amide 8(Trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-carbamic acid tert-butyl ester 95-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid(trans-4- dimethylamino-cyclohexyl)-amide 10(3aS,5R,6aR)-5-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester11 5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid [(S)-1-methyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide 12(3aR,5S,6aS)-5-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 135-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid[(S)-1-(1- methyl-piperidin-4-ylcarbamoyl)-ethyl]-amide 145-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid[(S)-1-(4- dimethylaminomethyl-phenyl)-ethyl]-amide 155-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid [1-(3-dimethylamino-propionyl)-piperidin-4-yl]-amide 165-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid[(S)-1-(5- dimethylaminomethyl-oxazol-2-yl)-ethyl]-amide 175-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid [1-(2-dimethylamino-acetyl)-piperidin-4-yl]-amide 185-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid {(S)-1-[methyl-(1-methyl-piperidin-4-ylmethyl)-carbamoyl]-ethyl}-amide 195-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid[(S)-2-(4- dimethylamino-piperidin-1-yl)-1-methyl-2-oxo-ethyl]-amide 205-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid {(S)-1-[(2-dimethylamino-ethyl)-methyl-carbamoyl]-ethyl}-amide 215-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid[(S)-1-(5- dimethylaminomethyl-oxazol-2-yl)-2-methyl- propyl]-amide 225-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid[(S)-1-(5- dimethylaminomethyl-oxazol-2-yl)-propyl]-amide 235-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid [1-(5-dimethylaminomethyl-oxazol-2-yl)-cyclopropyl]-amide 245-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid [1-(5-dimethylaminomethyl-oxazol-2-yl)-1-methyl-ethyl]-amide 255-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid [1-(2-dimethylamino-acetyl)-4-methyl-piperidin-4-yl]-amide 265-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid[trans-4- (2-dimethylamino-acetylamino)-cyclohexyl]-amide 275-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid{trans-4- [(2-dimethylamino-acetylamino)-methyl]-cyclohexyl}-amide 285-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylic acid {(S)-1-[methyl-(1-methyl-piperidin-4-yl)-carbamoyl]-ethyl}-amide 29(Trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-trimethyl-ammonium benzene sulfonate 30Benzyl-(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-dimethyl-ammonium bromide 31(Trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-ethyl-dimethyl-ammonium benzene sulfonate 324-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-1,1-dimethyl-piperidinium benzenesulfonate 33(R)-3-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-1,1-dimethyl-pyrrolidinium benzenesulfonate 34(S)-3-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-1,1-dimethyl-pyrrolidinium benzenesulfonate 354-(1-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-1,1-dimethyl-piperidinium benzene sulfonate 36(1S,3R,5R)-3-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane benzene sulfonate 37(3aS,5R,6aR)-5-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-2,2-dimethyl-octahydro-cyclopenta[c]pyrrolium benzene sulfonate384-((S)-1-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-1-methyl-pyridinium benzene sulfonate 39(1R,3S,5S)-3-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane benzene sulfonate 404-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-1,1-diethyl-piperidinium benzene sulfonate 41(Trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-trimethyl-ammonium benzene sulfonate 424-((S)-1-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-1-ethyl-pyridinium benzene sulfonate 43Benzyl-(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-dimethyl-ammonium bromide 44(Trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-ethyl-dimethyl-ammonium benzene sulfonate 45(Cis-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-trimethyl-ammonium benzene sulfonate 46Benzyl-(cis-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-dimethyl-ammonium bromide 474-(1-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-1-methyl-ethyl)-1-methyl-pyridinium benzene sulfonate 48(Cis-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-ethyl-dimethyl-ammonium benzene sulfonate 491-Benzyl-4-((S)-2-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionyl)-1-methyl-piperazin-1-ium bromide 504-((S)-2-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionyl)-1,1-dimethyl-piperazin-1-ium benzene sulfonate 512-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-7,7-dimethyl-7-azonia-spiro[3.5]nonane benzene sulfonate 524-((R)-1-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-1-methyl-pyridinium benzene sulfonate 53(Cis-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifiuoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-trimethyl-ammonium benzene sulfonate 54Benzyl-(cis-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifiuoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-dimethyl-ammonium bromide 55(Cis-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-ethyl-dimethyl-ammonium benzene sulfonate 56(3aR,5S,6aS)-5-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-2,2-dimethyl-octahydro-cyclopenta[c]pyrrolium benzene sulfonate 574-((S)-2-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionylamino)-1,1-dimethyl-piperidinium benzene sulfonate 58[4-((S)-1-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-benzyl]-trimethyl-ammonium benzene sulfonate 59[4-((S)-1-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-benzyl]-trimethyl-ammonium benzene sulfonate 60[5-((S)-1-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-[1,2,4]oxadiazol-3-ylmethyl]-trimethyl-ammonium benzene sulfonate 61[2-(4-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidin-1-yl)-2-oxo-ethyl]-trimethyl-ammonium benzene sulfonate 624-{[((S)-2-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionyl)-methyl-amino]-methyl}-1,1-dimethyl-piperidinium benzenesulfonate 63[5-((S)-1-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-[1,3,4]oxadiazol-2-ylmethyl]-trimethyl-ammonium benzene sulfonate 64[2-((S)-1-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-oxazol-5-ylmethyl]-trimethyl-ammonium benzene sulfonate 65[3-(4-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidin-1-yl)-3-oxo-propyl]-trimethyl-ammonium benzene sulfonate 669-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-3,3-dimethyl-3-azonia-spiro[5.5]undecane benzene sulfonate 67(Cis-3-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclobutylmethyl)-trimethyl-ammonium benzene sulfonate 68(Trans-3-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclobutylmethyl)-trimethyl-ammonium benzene sulfonate 69[1-((S)-2-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]-trimethyl-ammonium benzene sulfonate 70Benzyl-[1-((S)-2-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]-dimethyl-ammonium bromide 71{2-[((S)-2-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionyl)-methyl-amino]-ethyl}-trimethyl-ammonium benzene sulfonate 72(Trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-dimethyl-[1,2,4]oxadiazol-3-ylmethyl-amnionium chloride 73[2-((S)-1-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-2-methyl-propyl)-oxazol-5-ylmethyl]-trimethyl-ammonium benzene sulfonate74[2-((S)-1-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propyl)-oxazol-5-ylmethyl]-trimethyl-ammonium benzene sulfonate 75(4-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-dimethyl-(5-methyl-isoxazol-3-ylmethyl)-ammonium chloride 76(4-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-dimethyl-ammoniumchloride 77{2-[(Trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexanecarbonyl)-amino]-ethyl}-trimethyl-ammonium benzene sulfonate78 [2-(1-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-1-methyl-ethyl)-oxazol-5-ylmethyl]-trimethyl-ammonium benzene sulfonate 79[2-(1-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclopropyl)-oxazol-5-ylmethyl]-trimethyl-ammonium benzene sulfonate 80{2-[(Cis-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexanecarbonyl)-amino]-ethyl}-trimethyl-ammonium benzene sulfonate81{2-[(Cis-3-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclobutanecarbonyl)-amino]-ethyl}-trimethyl-ammonium benzene sulfonate82[2-(Trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexanecarbonyloxy)-ethyl]-trimethyl-ammonium benzene sulfonate 83{2-[(Trans-3-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclobutanecarbonyl)-amino]-ethyl}-trimethyl-ammonium benzene sulfonate84 [2-(4-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-trimethyl-ammonium benzene sulfonate85 ±[2-(1-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-thiazol-4-ylmethyl]-trimethyl-ammonium benzene sulfonate 86{[(Trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-carbamoyl]-methyl}-trimethyl-ammonium benzenesulfonate 87[(Trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylcarbamoyl)-methyl]-trimethyl-ammonium benzene sulfonate 88[1-(Trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifiuoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexanecarbonyl)-piperidin-4-yl]-trimethyl-ammonium benzenesulfonate 89{2-[(Trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexanecarbonyl)-methyl-amino]-ethyl}-trimethyl-ammonium benzenesulfonate 904-[(Trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexanecarbonyl)-amino]-1,1-dimethyl-piperidinium benzene sulfonate914-[((S)-2-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionyl)-methyl-amino]-1,1-dimethyl-piperidinium benzene sulfonate 92{2-[(4-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidine-1-carbonyl)-amino]-ethyl}-trimethyl-ammonium benzenesulfonate 93[2-(4-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidine-1-carbonyloxy)-ethyl]-trimethyl-ammonium benzene sulfonate 94[2-(4-{[1-(4-Cyano-phenyl)-5′-methyl-2′-oxo-1′-(3-trifluoromethyl-phenyl)-1′,2′-dihydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-amino}-piperidin-1-yl)-2-oxo-ethyl]-trimethyl-ammonium benzene sulfonate

The therapeutic utility of the present compounds is pertinent to anydisease that is known to be at least partially mediated by the action ofhuman neutrophil elastase. For example, the present compounds can bebeneficial in the treatment of chronic obstructive pulmonary disease(COPD), cystic fibrosis (CF), bronchiectasis, acute respiratory distresssyndrome (ARDS), pulmonary emphysema, pneumonia and lung fibrosis.

Compounds of the present invention are useful for treatment ofinflammatory respiratory disorders, for example asthma (mild, moderateor severe), steroid resistant asthma, bronchitis, chronic obstructivepulmonary disease (COPD), cystic fibrosis (CF), pulmonary edema,pulmonary embolism, pneumonia, pulmonary sarcoidosis, pulmonaryemphysema, silicosis, pulmonary fibrosis, pulmonary hypertension,respiratory failure, acute respiratory distress syndrome (ARDS),emphysema, chronic bronchitis, tuberculosis, aspergillosis and otherfungal infections, hypersensitivity pneumonitis, vasculitic andthrombotic disorders of the lung vasculature, antitussive activityincluding treatment of chronic cough associated with inflammatory andsecretory conditions of the airways, infection due to respiratorysyncytial virus, influenza, coronavirus (including severe acuterespiratory syndrome, SARS) and adenovirus, bronchiectasis and lungcancer.

The present invention is also concerned with pharmaceutical formulationscomprising, as an active ingredient, a compound of the invention. Othercompounds can be combined with compounds of this invention for theprevention and treatment of inflammatory diseases of the lung. Thus, thepresent invention is also concerned with pharmaceutical compositions forpreventing and treating inflammatory diseases of the lung comprising atherapeutically effective amount of a compound of the invention and oneor more other therapeutic agents.

Suitable therapeutic agents for a combination therapy with compounds ofthe invention include: (1) a corticosteroid, for example budesonide,beclomethasone, beclomethasone (e.g., as the mono or the dipropionateester), flunisolide, fluticasone (e.g. as the propionate or furoateester), Ciclesonide, mometasone (e.g. as the furoate ester), mometasonedesonide, rofleponide, hydrocortisone, prednisone, prednisolone, methylprednisolone, naflocort, deflazacort, halopredone acetate, fluocinoloneacetonide, fluocinonide, clocortolone, tipredane, prednicarbate,alclometasone dipropionate, halometasone, rimexolone, deprodonepropionate, triamcinolone, betamethasone, fludrocortisone,desoxycorticosterone, rofleponide, etiprednol dicloacetate and the like.Steroid drugs can additionally include steroids in clinical orpre-clinical development for respiratory diseases such as GW-685698,GW-799943, GSK 870086, QAE397, NCX-1010, NCX-1020, NO-dexamethasone,PL-2146, NS-126 (formerly ST-126). Steroid drugs can also additionallyinclude next generation molecules in development with reduced sideeffect profiles such as selective glucocorticoid receptor agonists(SEGRAs), including ZK-216348 and AZD5423; (2) a β2-adrenoreceptoragonist, such as albuterol, bambuterol, terbutaline, fenoterol,formoterol, formoterol fumarate, salmeterol, salmeterol xinafoate,arformoterol, arfomoterol tartrate, indacaterol (QAB-149), carmoterol,BI 1744 CL, GSK159797 (milveterol), GSK59790, GSK159802, GSK642444(vilanterol), GSK678007, GSK96108, clenbuterol, procaterol, bitolterol,LAS100977 (abediterol), BI1744CL (olodaterol) and brodxaterol; (3) aleukotriene modulator, for example montelukast, zafirlukast orpranlukast; (4) anticholinergic agents, for example selectivemuscarinic-3 (M3) receptor antagonists such as ipratropium bromide,tiotropium, tiotropium bromide (Spiriva®), glycopyrronium bromide,aclidinium bromide, LAS34273, GSK656398, GSK233705, GSK 573719(umeclidinium), LAS35201, QAT370 and oxytropium bromide; (5)phosphodiesterase-IV (PDE-IV) inhibitors, for example roflumilast,cilomilast or theophylline; (6) an antitussive agent, such as codeine ordextramorphan; and (7) a non-steroidal anti-inflammatory agent (NSAID),for example ibuprofen or ketoprofen; (8) a mucolytic, for example Nacetyl cysteine or fudostein; (9) an expectorant/mucokinetic modulator,for example ambroxol, hypertonic solutions (e.g. saline or mannitol) orsurfactant; (10) a peptide mucolytic, for example recombinant humandeoxyribonuclease I (dornase-alfa and rhDNase) or helicidin; (11)antibiotics, for example azithromycin, tobramycin and aztreonam; and(12) p38 Mitogen Activated Protein (MAP) kinase inhibitors, such as GSK856553 and GSK 681323; (13) inhibitors of Janus Kinases (JAK) such asCP-690550 or GLPG0634; (14) Spleen Tyrosine Kinase (SYK) inhibitors suchas R406, R343 or PRT062607; (15) inhibitors of delta and/or gammaisoforms of Phosphatidylinositol 3-kinase (PI3K).; (16) anti-retroviralagents such as ribavirin, zanamivir or laninamivir; (17) PPAR-γ agonistssuch as pioglitazone and rosiglitazone.

In one aspect, the invention concerns the use of inhaled administrationof compounds of the invention in combination with otheranti-inflammatory drugs and bronchodilator drug combinations (i.e.triple combination product), including but not limited to salmeterolxinafoate/fluticasone propionate (Advair/Seretide®),vilanterol/fluticasone furoate (BREO ELLIPTA™), formoterolfumarate/budesonide (Symbicort®), formoterol fumarate/mometasonefuroate, formoterol fumarate/beclometasone dipropionate (Foster®),formoterol fumarate/fluticasone propionate (FlutiForm®),Indacaterol/mometasone furoate, Indacaterol/QAE-397, GSK159797/GSK685698, GSK159802/GSK 685698, GSK642444/GSK 685698, formoterolfumarate/ciclesonide, arformoterol tartrate/ciclesonide.

In another aspect, the invention concerns the use of inhaledadministration of compounds of the invention in combination with otherbronchodilator drug combinations, particularly β₂ agonist/M₃ antagonistcombinations (i.e. triple combination product), including but notlimited to salmeterol xinafoate/tiotropium bromide, formoterolfumarate/tiotropium bromide, formoterol fumarate/glycopyrrolate (PT003),BI 1744 CL/tiotropium bromide, indacaterol/NVA237, indacterol/QAT-370,formoterol/LAS34273, umeclidinium/vilanterol (Anoro™), GSK159797/GSK573719, GSK159802/GSK 573719, GSK642444/GSK 573719, GSK159797/GSK233705, GSK159802/GSK 233705, GSK642444/GSK 233705.

The weight ratio of the first and second active ingredients can bevaried and will depend upon the effective dose of each ingredient.Generally, an effective dose of each will be used.

The magnitude of prophylactic or therapeutic dose of a compound of theinvention will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound and its routeof administration, and will generally be determined by clinical trial asrequired in the pharmaceutical art. It will also vary according to theage, weight and response of the individual patient. In general, thedaily dose range will lie within the range of from about 0.001 mg toabout 100 mg per kg body weight of a mammal, preferably 0.01 mg to about50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single ordivided doses. On the other hand, it can be necessary to use dosagesoutside these limits in some cases.

Another aspect of the present invention concerns pharmaceuticalcompositions which comprise a compound of the invention and apharmaceutically acceptable carrier. The pharmaceutical compositions ofthe present invention comprise a compound of the present invention as anactive ingredient or a pharmaceutically acceptable salt thereof, and canalso contain a pharmaceutically acceptable carrier and optionally othertherapeutic ingredients.

Any suitable route of administration can be employed for providing amammal, especially a human, with an effective dosage of a compound ofthe invention. In therapeutic use, the active compound can beadministered by any convenient, suitable or effective route. Suitableroutes of administration are known, and include oral, intravenous,rectal, parenteral, topical, ocular, nasal, buccal and pulmonary (byinhalation).

Compositions suitable for administration by inhalation are known, andcan include carriers and/or diluents that are known for use in suchcompositions. The composition can contain 0.01-99% by weight of activecompound. Preferably, a unit dose comprises the active compound in anamount of 1 μg to 10 mg.

The most suitable dosage level can be determined by any known suitablemethod. It will be understood, however, that the specific amount for anyparticular patient will depend upon a variety of factors, including theactivity of the specific compound that is used, the age, body weight,diet, general health and sex of the patient, time of administration, theroute of administration, the rate of excretion, the use of any otherdrugs, and the severity of the disease to be treated.

For delivery by inhalation, the active compound is preferably in theform of microparticles. They can be prepared by a variety of techniques,including spray-drying, freeze-drying and micronization.

By way of example, a composition of the invention can be prepared as asuspension for delivery from a nebuliser or as an aerosol in a liquidpropellant, for example for use in a pressurised metered dose inhaler(PMDI). Propellants suitable for use in a PMDI are known and includeCFC-12, HFA-134a, HFA-227, HCFC-22 (CCl2F2) and HFA-152 (CH4F2 andisobutane).

In a preferred embodiment, a composition is in dry powder form, fordelivery using a dry powder inhaler (DPI). Many types of DPI are known.

Microparticles for delivery by administration can be formulated withexcipients that aid delivery and release. For example, in a dry powderformulation, microparticles can be formulated with large carrierparticles that aid flow from the DPI into the lung. Suitable carrierparticles are known, and include lactose particles; they can have a massmedian aerodynamic diameter of greater than 90 μm.

In the case of an aerosol-based formulation, a preferred composition is:

Compound of the invention 24 mg/canister Lecithin, NF Liq. Conc. 1.2mg/canister Trichlorofluoromethane, NF 4.025 g/canisterDichlorodifluoromethane, NF 12.15 g/canister.

The compounds of the present invention can be used in combination withother drugs that are used in the treatment/prevention/suppression oramelioration of the diseases or conditions for which present compoundsare useful. Such other drugs can be administered, by a route and in anamount commonly used therefore, contemporaneously or sequentially with acompound of the invention. When a compound of the invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe invention is preferred. Accordingly, the pharmaceutical compositionsof the invention include those that also contain one or more otheractive ingredients, in addition to a compound of the invention.

The agents of the present invention can be administered in inhaled form.Aerosol generation can be carried out using, for example,pressure-driven jet atomizers or ultrasonic atomizers, preferably usingpropellant-driven metered aerosols or propellant-free administration ofmicronized active compounds from, for example, inhalation capsules orother “dry powder” delivery systems.

The active compounds can be dosed as described depending on the inhalersystem used. In addition to the active compounds, the administrationforms can additionally contain excipients, such as, for example,propellants (e.g. Frigen in the case of metered aerosols),surface-active substances, emulsifiers, stabilizers, preservatives,flavorings, fillers (e.g. lactose in the case of powder inhalers) or, ifappropriate, further active compounds.

For the purposes of inhalation, a large number of systems are availablewith which aerosols of optimum particle size can be generated andadministered, using an inhalation technique which is appropriate for thepatient. In addition to the use of adaptors (spacers, expanders) andpear-shaped containers (e.g. Nebulator®, Volumatic®), and automaticdevices emitting a puffer spray (Autohaler®), for metered aerosols, inparticular in the case of powder inhalers, a number of technicalsolutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or theinhalers for example as described EP-A-0505321).

Procedure for the Preparation of Compounds of Formula (I)

The present invention further provides a process for the preparation ofa compound of formula (I) or a pharmaceutically acceptable salt orquaternary salt thereof as defined above. Compounds of the invention (I)may be prepared according to routes illustrated below in Scheme A.

The skilled person may introduce, where appropriate, suitable variationsto the conditions specifically described in the experimental in order toadapt the synthetic routes to the provision of further compounds of theinvention. Such variations may include, but are not limited to, use ofappropriate starting materials to generate different compounds, changesin the solvent and temperature of reactions, replacements of reagentswith analogous chemical role, introduction or removal ofprotection/deprotection stages of functional groups sensitive toreaction conditions and reagents.

Also, introduction or removal of specific synthetic steps oriented tofurther functionalization of the chemical scaffold may be contemplatedand is included within the scope of the present invention. Processeswhich can be used and are described and reported in the Examples andSchemes, should not be viewed as limiting the scope of the syntheticmethods available for the preparation of the compounds of the invention.

Compounds used as starting materials or intermediates may becommercially available, their preparation may be specifically describedin the literature or they may be prepared according to known methods. Insome instances, procedures for the preparation of intermediates orstarting materials may be also provided in the experimental.

The process described is particularly advantageous as it is susceptibleof being properly modulated, through any known proper variant, so as toobtain any of the desired compounds of the invention. Such variants arecomprised within the scope of the present invention.

From all of the above, it should be clear that any of the describedgroups may be present as such or in any properly protected form.

In particular, functional groups present in the intermediate andcompounds and which could generate unwanted side reaction andby-products, need to be properly protected before the alkylation,acylation, coupling or sulfonylation takes place. Likewise, subsequentdeprotection of those same protected groups may follow upon completionof the said reactions.

In the present invention, unless otherwise indicated, the term“protecting group” designates a protective group adapted to preserve thefunction of the group it is bound to. Typically, protective groups areused to preserve amino, hydroxyl, or carboxyl functions. Appropriateprotecting groups may thus include, for example, benzyl,benzyloxycarbonyl, t-butoxycarbonyl, alkyl or benzyl esters or the like,which are well known (see, for a general reference, T. W. Green;Protective Groups in Organic Synthesis (Wiley, N.Y. 1981), which isincorporated herein by reference in its entirety).

Likewise, selective protection and deprotection of any of the saidgroups, for instance including carbonyl, hydroxyl or amino groups, maybe accomplished according to very well-known methods commonly employedin organic synthetic chemistry.

From all of the above, it should be clear that the above process,comprehensive of any variant thereof for the preparation of suitablecompounds of the invention, may be conveniently modified so that toadapt the reaction conditions to the specific needs, for instance bychoosing appropriate condensing agents, solvents and protective groups,as the case may be.

In the following Scheme, for compounds of formula (I) to (X), unlessotherwise indicated, groups A and X have the same meanings as describedfor compounds of formula (I) above.

Compounds of formula (I) may be prepared from compounds of formula (III)by reaction with para-nitrophenol chloroformate in the presence of abase such as triethylamine in a solvent such as dichloromethane at anappropriate temperature of between 0° C. and the boiling point of thesolvent. This gives activated carbamate of formula (II) which cansubsequently be reacted with an amine of formula X—NH₂ in a solvent suchas dichloromethane at an appropriate temperature of between 0° C. andthe boiling point of the solvent to give compounds of formula (I).

Compounds of formula (I) may also be prepared from compounds of formula(III) by reaction with an appropriate isocyanate of formula X—NCO orequivalent in a suitable solvent such as dichloromethane at anappropriate temperature of between 0° C. and the boiling point of thesolvent.

In the instances where compounds of formula (I) contain a quaternaryammonium moiety then a quaternisation step may also be used. This can becarried out by reaction with an alkylating agent such as methylbenzenesulphonate or benzyl bromide in a solvent such as THF at anappropriate temperature between ambient and the boiling point of thesolvent.

A compound of formula (III) may be synthesized from a compound offormula (IV) by deprotection using an acid such as an aqueoushydrochloric acid solution in a solvent such as acetone at anappropriate temperature between 0° C. and the boiling point of thesolvent.

A compound of formula (IV) may be synthesized from a compound of formula(V) by palladium coupling with a suitable partner fragment of formula(VI) wherein M may be, for example, a group such as —Sn(n-Bu)₃. Thecoupling can be carried out with a catalyst such as Pd(PPh₃)₄ in anappropriate solvent such as 1,4-dioxane at a suitable temperaturebetween ambient and the boiling point of the solvent. If M is halide,for example bromide, then suitable reagents such as2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)palladium(II)dichloride and tetrahydroxydiboron in the presence of potassium acetateand K₂CO₃ in an appropriate solvent such as ethanol at a suitabletemperature between ambient and the boiling point of the solvent, may beused.

A compound of formula (V) may be synthesized from a compound of formula(VII) by bromination using a reagent such as N-bromosuccinimide in anappropriate solvent such as acetonitrile at a suitable temperaturebetween 0° C. and the boiling point of the solvent.

A compound of formula (VII) may be synthesized from a compound offormula (VIII) by ethylation using a regent such as Meerwein's reagent(Et₃O⁺BF₄ ⁻) in an appropriate solvent such as dichloromethane at asuitable temperature between 0° C. and the boiling point of the solvent.

A compound of formula (VIII) may be synthesized from a compound offormula (IX) using a strong base such as sodium hydride in anappropriate solvent such as tetrahydrofuran/acetonitrile at a suitabletemperature between 0° C. and the boiling point of the solvent.

A compound of formula (IX) maybe synthesized from a compound of formula(X) by reaction with an amine such as propargylamine in an appropriatesolvent such as acetonitrile at a suitable temperature between 0° C. andthe boiling point of the solvent.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

Reactions were not carried out under an inert atmosphere unlessspecified and all solvents and commercial reagents were used asreceived.

Purification by chromatography refers to purification using theCombiFlash® Companion purification system or the Biotage SP1purification system. Where products were purified using an Isolute® SPESi II cartridge, ‘Isolute SPE Si cartridge’ refers to a pre-packedpolypropylene column containing unbonded activated silica with irregularparticles with average size of 50 μm and nominal 60 Å porosity.Fractions containing the required product (identified by TLC and/or LCMSanalysis) were pooled and concentrated in vacuo. Where HPLC was used forpurification (Purification by MDAP) fractions containing the requiredproduct (identified by TLC and/or LCMS analysis) were pooled, the bulkof the organic fraction removed by evaporation, and the remainingaqueous fraction lyophilised, to give the final product. Alternativelythe pooled product fraction was evaporated to dryness under reducedpressure. Where thin layer chromatography (TLC) has been used, it refersto silica gel TLC using plates, typically 3×6 cm silica gel on aluminiumfoil plates with a fluorescent indicator (254 nm), (e.g. Fluka 60778).Microwave experiments were carried out using a Biotage Initiator 60™which uses a single-mode resonator and dynamic field tuning. Temperaturefrom 40-250° C. can be achieved, and pressures of up to 30 bar can bereached.

NMR spectra were obtained on a Varian Unity Inova 400 spectrometer witha 5 mm inverse detection triple resonance probe operating at 400 MHz oron a Bruker Avance DRX 400 spectrometer with a 5 mm inverse detectiontriple resonance TXI probe operating at 400 MHz or on a Bruker AvanceDPX 300 spectrometer with a standard 5 mm dual frequency probe operatingat 300 MHz. Shifts are given in ppm relative to tetramethylsilane.

Compound names were generated using ACD/Name 2012 or AutoNom.

Analytical LC-MS Conditions LC-MS Method 1

The Waters ZQ quadrupole mass spectrometer with a C18-reverse-phasecolumn (30×4.6 mm Phenomenex Luna 3 μm particle size), elution with A:water+0.1% formic acid; B: MeCN+0.1% formic acid. Gradient:

Gradient - Time flow (mL/min) % A % B 0.00 2.0 95 5 0.30 2.0 95 5 4.302.0 5 95 5.30 2.0 5 95 5.80 2.0 95 5 6.00 2.0 95 5

Detection—MS, UV (200 μl/min split to the ESI source with in-line HP1100PDA detector)

MS ionization method—Electrospray (positive and negative ion)

LC-MS Method 2

Waters Micromass ZMD quadrupole mass spectrometer with aC18-reverse-phase column (30×4.6 mm Phenomenex Luna 3 μm particle size),elution with A: water+0.1% formic acid; B: MeCN+0.1% formic acid.Gradient:

Gradient - Time flow(mL/min) % A % B 0.00 2.0 95 5 0.50 2.0 95 5 4.502.0 5 95 5.50 2.0 5 95 6.00 2.0 95 5

Detection—MS, ELS, UV (200 μl split to MS with in-line UV detector)

MS ionization method—Electrospray (positive and negative ion)

LC-MS Method 3

Waters Micromass ZQ2000 mass spectrometer with a C18-reverse-phasecolumn (100×2.1 mm Acquity BEH with 1.7 μm particle size) maintained at40° C., elution with A: water+0.1% formic acid; B: MeCN+0.1% formicacid. Alternatively, where specified, a C18-reverse-phase (100×2.1 mmAcquity UPLC BEH Shield 1.7 μm particle size) column was used.

Gradient:

Gradient - Time flow (mL/min) % A % B 0.00 0.4 95 5 0.40 0.4 95 5 6.000.4 5 95 6.80 0.4 5 95 7.00 0.4 95 5 8.00 0.4 95 5

Detection—MS, UV PDA

MS ionization method—Electrospray (positive/negative ion).

LC-MS Method U1

Acquity H-Class (quaternary pump/PDA detector) plus QDa MassSpectrometer with an Acquity UPLC BEH C18-reverse-phase column (1.7 μmparticle size, 50×2.1 mm at 50° C.), elution with A: water+0.1% formicacid; B: MeCN+0.1% formic acid.

Gradient:

Gradient - Time flow (mL/min) % A % B 0.00 1.0 97 3 1.50 1.0 1 99 1.901.0 1 99 2.00 1.0 97 3 2.50 1.0 97 3

Detection—MS, UV

MS ionization method—Electrospray (positive and negative ion).

LC-MS Method U2

Acquity H-Class (quaternary pump/PDA detector) plus QDa MassSpectrometer with an Acquity UPLC BEH C18-reverse-phase column (1.7 μmparticle size, 50×2.1 mm at 40° C.), elution with A: water+0.1% formicacid; B: MeCN+0.1% formic acid.

Gradient:

Gradient - Time flow (mL/min) % A % B 0.00 1.0 97 3 1.50 1.0 1 99 1.901.0 1 99 2.00 1.0 97 3 2.50 1.0 97 3

Detection—MS, UV

MS ionization method—Electrospray (positive and negative ion).

LC-MS Method 7

HP1100 (quaternary pump/PDA detector) plus ZQ Mass Spectrometer with aPhenomenex Luna C18(2) 3μ, 30×4.6 mm column, elution with A: water+0.1%formic acid; B: MeCN+0.1% formic acid.

Gradient:

Gradient - Time flow % A % B 0.00 2.0 95 5 0.30 2.0 95 5 4.30 2.0 5 955.30 2.0 5 95 5.80 2.0 95 5 6.00 2.0 95 5

Detection—MS, UV

MS ionization method—Electrospray (positive and negative ion)

Abbreviations Used in the Experimental Section

DCM Dichloromethane

DIPEA Di-isopropylethylamine

DMF N,N-dimethylformamide

DMSO Dimethylsulphoxide

Et₂O Diethyl ether

EtOAc Ethyl acetate

h Hour

HPLC High performance liquid chromatography

IMS Industrial methylated spirits

LC-MS Liquid chromatography-mass spectrometry

MeCN Acetonitrile

MDAP Mass Directed Automatic Purification

Min Minutes

NBS N-Bromosuccinimide

Rt Retention time

RT Room temperature

THF Tetrahydrofuran

In the procedures that follow, some of the starting materials areidentified through an “Intermediate” or “Example” number. The startingmaterial may not necessarily have been prepared from the batch referredto.

When reference is made to the use of a “similar” or “analogous”procedure such a procedure may involve minor variations, for examplereaction temperature, reagent/solvent amount, reaction time, work-upconditions or chromatographic purification conditions.

The present invention will now be further described by the followingexamples.

Intermediate A.4-(5-{5-Methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile

Intermediate A1. 1-Prop-2-yn-1-yl-3-[3-(trifluoromethyl)phenyl]urea

A solution of propargyl amine (4.41 g, 5.13 mL, 80 mmol) in MeCN (30 mL)was added to a stirred solution of 3-(trifluoromethyl)phenyl isocyanate(15.0 g, 12.12 mL, 80 mmol) in MeCN (60 mL) under a nitrogen atmosphere.The reaction mixture was cooled with a RT cooling bath and the rate ofaddition was such that the internal temperature did not exceed 35° C.After 1.5 h the mixture was concentrated in vacuo. EtOAc (10 ml) wasadded to the residue and the mixture was sonicated for 2 minutes. Theresultant slurry was diluted with cyclohexane (40 ml). The mixture wasstirred for 10 minutes and the solid was then recovered by filtration.The mother liquors were concentrated in vacuo and the residue dissolvedin EtOAc (10 mL). Dilution with cyclohexane (90 ml) precipitated asecond batch of product which was recovered by filtration. The twobatches were combined as an ethyl acetate solution and concentrated invacuo to afford the title compound as a fawn solid (16.65 g).

LCMS (Method 2): Rt=3.22 min, m/z 243 [M+H]⁺

Intermediate A2.5-Methyl-1-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-imidazol-2-one

A solution of 1-prop-2-yn-1-yl-3-[3-(trifluoromethyl)phenyl]urea(intermediate A1) (11.2 g, 46 mmol) in THF (60 mL) and acetonitrile (120mL) was added, under a nitrogen atmosphere, to a stirred suspension ofsodium hydride (60% dispersion in mineral oil) (4.62 g, 115 mmol) in THF(60 mL) at such a rate that gas evolution was not over-vigorous and theinternal temperature remained below 30° C. The mixture was stirred at RTfor 2.5 h, a thick precipitate having formed within 1 h. The reactionmixture was cautiously quenched with water (15 mL) and the resultingsolution was treated with 1 M hydrochloric acid (150 mL, 150 mmol). Themixture was stirred for 4 hours then allowed to stand for 15 hours.Saturated brine (150 mL) was added and the phases were partitioned. Theaqueous phase was extracted with EtOAc (100 mL). The combined organicphase was washed with saturated brine (100 mL), dried (sodium sulfate)and concentrated in vacuo. The residue was triturated with EtOAc (33mL). The resultant solid was taken into DCM and filtered. The filtratewas concentrated in vacuo to afford the title compound (10.0 g) as afawn solid.

LCMS (Method 1): Rt=2.63 min, m/z 243 [M+H]⁺

Intermediate A3.2-Ethoxy-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-imidazole

A solution of triethyloxonium tetrafluoroborate (9.0 g, 47 mmol) in DCM(62 mL) was added to a stirred solution of5-methyl-1-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-imidazol-2-one(Intermediate A2, 9.0 g, 37 mmol) in DCM (124 mL) under a nitrogenatmosphere. The solution was stirred at RT for 2.5 h then treated withwater (50 mL) then 1 M sodium hydroxide (50 mL). The phases werepartitioned. The aqueous phase was washed with DCM (2×50 mL). Thecombined organic phase was dried (sodium sulfate). The solution of thecrude product was filtered through 2×50 g flash SCX 2 cartridges. Eachcartridge was rinsed with 10% methanol in DCM (100 mL) then the productfraction was eluted with 2M methanolic ammonia solution (100 mL). Thefractions recovered with methanolic ammonia were combined andconcentrated in vacuo to afford the title compound (7.92 g) as a brownsolid.

LCMS (Method 1): Rt=2.41 min, m/z 271 [M+H]⁺

Intermediate A4.4-Bromo-2-ethoxy-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-imidazole

A solution of NBS (5.16 g, 29 mmol) in MeCN (60 mL) was added to astirred solution of2-ethoxy-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-imidazole(Intermediate A3, 7.92 g, 29 mmol) in MeCN (115 mL) at such a rate thatthe internal temperature of the mixture did not exceed 25° C. (a RTcooling bath was used). After 0.5 h the mixture was diluted with water(50 mL) and saturated sodium carbonate (aq) (50 mL). Ethyl acetate (50mL) was added. The mixture was stirred vigorously then the phases wereseparated. The organic phase was washed with saturated brine (50 mL),dried (sodium sulfate) and concentrated in vacuo. The residue was takeninto dichloromethane and filtered through a 25 g Si II SPE cartridge.The cartridge was washed with DCM and 10% EtOAc in DCM. The filtrate wasconcentrated in vacuo to afford the title compound as an off-white solid(8.93 g).

LCMS (Method 1): Rt=3.86 min, m/z 349 [M(⁷⁹Br)+H]⁺

Intermediate A5.4-(5-{2-Ethoxy-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile

A solution of4-bromo-2-ethoxy-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-imidazole(Intermediate A4, 3.14 g, 9 mmol) and4-(5-tributylstannyl-pyrazol-1-yl)-benzonitrile (see WO2014009425A1,which is incorporated herein by reference in its entirety) (6.19 g, 13.5mmol) in 1,4-dioxane (45 mL) was degassed by bubbling argon through thesolution for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.52g, 0.45 mmol) was added and after a further period of degassing themixture was heated at 94° C. under an argon atmosphere during 17 h. Themixture was cooled to RT and filtered through a 50 g flash SCX 2cartridge. The cartridge was eluted with DCM, 10% methanol in DCM then a1:1 mixture of 2M ammonia in methanol and DCM. Concentration of theappropriate fractions in vacuo afforded the crude product. This wastriturated with cyclohexane and dried in vacuo to afford the titlecompound (3.01 g).

LCMS (Method 1): Rt=3.84 min, m/z 438 [M+H]⁺

4-(5-{5-Methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile(Intermediate A)

A suspension of4-(5-{2-ethoxy-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile(0.71 g, 1.6 mmol) in acetone (10 mL) and 1M hydrochloric acid (1.6 mL)was heated at 60° C. for 14 h. The mixture was cooled, diluted withacetone (50 mL) and filtered through a 5 g flash NH2 column. Thefiltrate was concentrated in vacuo. The residue was twice taken intoacetonitrile and reconcentrated. The residue was triturated with acetone(10 mL) and dried in vacuo to afford the title compound (0.45 g)

LCMS (Method 3): Rt=4.32 min, m/z 410.1 [M+H]⁺

¹H NMR (400 MHz, CDCl₃): δ 9.27 (1H, br s), 7.78 (1H, d J=1.8 Hz),7.73-7.63 (4H, m), 7.60-7.56 (3H, m), 7.49 (1H, dJ=7.5 Hz), 6.56 (1H, dJ=1.8 Hz), 1.84 (3H, S).

Intermediate B.(S)-1-(3-Dimethylaminomethyl-[1,2,4]oxadiazol-5-yl)-ethylamine TFA salt

Intermediate B1.[(S)-1-(3-Dimethylaminomethyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamicacid tert-butyl ester

A solution of 2-(dimethylamino)-N-hydroxyethanimidamide (500 mg, 4.27mmol) and Boc-alanine (890 mg, 4.70 mmol) was formed in dichloromethane(20 mL) with N,N-diisopropylethylamine (1.1 g, 8.54 mmol). HATU (1.95 g,5.12 mmol) was added and the mixture stirred at ambient temperature for1 h then was headed at reflux for 1 h. The mixture was allowed to coolto RT then partitioned between DCM and sat. aqueous sodium bicarbonate.The organic phase was washed with brine, dried over MgSO₄ thenevaporated. This material was then dissolved in Dioxane (10 mL) andheated at reflux for 4 h. The mixture was then allowed to cool anddiluted with ethyl acetate, washed with 10% aqueous potassium carbonate,brine, dried over MgSO₄ then evaporated. Purification by flash columnchromatography (40 g Si cartridge) eluting with a gradient of 0-10% (2NNH3 in MeOH) in DCM gave Intermediate B1 as a white solid (230 mg, 20%)

LCMS (Method U1): Rt=0.70 min, m/z 271.2 [M+H]⁺

(S)-1-(3-Dimethylaminomethyl-[1,2,4]oxadiazol-5-yl)-ethylamine TFA salt

Intermediate B1 (230 mg, 0.85 mmol) was dissolved in DCM (6 mL).Trifluoroacetic acid (2 mL) was added and the mixture stirred for 2 h atambient temperature. Evaporation gave Intermediate B containing ˜4 eq ofTFA (320 mg, 60%).

¹H NMR (400 MHz, d6-DMSO): δ□ 9.01 (3H, br s), 5.05-4.96 (1H, m), 4.68(2H, s), 2.90 (6H, s), 1.64 (3H, d, J=7.0).

Intermediate C.(S)-1-(5-Dimethylaminomethyl-[1,3,4]oxadiazol-2-yl)-ethylamine TFA salt

Intermediate C1.{(S)-2-[N′-(2-Dimethylamino-acetyl)-hydrazino]-1-methyl-2-oxo-ethyl}-carbamicacid tert-butyl ester

A solution of Boc-Alanine (1 g, 5.3 mmol) was formed in DCM (40 mL). EDChydrochloride (1.02 g, 5.3 mmol) was added followed by1-hydroxybenzotriazole hydrate (716 mg, 5.3 mmol) and the mixturestirred for 5 mins. N,N-diisopropylethylamine (1.85 mL, 10.6 mmol) wasadded giving a yellow solution. Girard's Reagent D (1.1 g, 5.8 mmol) wasadded and the mixture stirred for 24 h. The mixture was partitionedbetween DCM and sat. aqueous sodium bicarbonate The organic phase wasisolated using a phase separation cartridge and evaporated. Purificationby flash column chromatography (40 g Si cartridge) eluting with agradient of 0-10% (2N NH3 in MeOH) in DCM gave Intermediate C1 as acolourless gum (870 mg, 57%).

¹H NMR (400 MHz, CDCl₃): δ 8.63 (1H, br s), 5.00-4.89 (1H, m), 4.34-4.22(1H, m), 3.08 (2H, s), 2.34 (6H, s), 1.46 (9H, s), 1.41 (3H, d, J=7.1Hz).

Intermediate C2.[(S)-1-(5-Dimethylaminomethyl-[1,3,4]oxadiazol-2-yl)-ethyl]-carbamicacid tert-butyl ester

A solution of Intermediate C1 (288 mg, 1 mmol) was formed in DCM (10mL). Burgess Reagent (357 mg, 1.5 mmol) was added and the mixturestirred over night at ambient temperature. The mixture was partitionedbetween water and DCM. The organic phase was isolated using a phaseseparation cartridge and evaporated. Purification by flash columnchromatography (12 g Si cartridge) eluting with a gradient of 0-10% (2NNH3 in MeOH) in DCM gave Intermediate C2 as a colourless oil (260 mg,96%).

¹H NMR (400 MHz, CDCl₃): δ 5.09 (2H, br s), 3.75 (2H, s), 2.35 (6H, s),1.59 (3H, m, partially obscured by water peak), 1.45 (9H, s).

(S)-1-(5-Dimethylaminomethyl-[1,3,4]oxadiazol-2-yl)-ethylamine TFA salt

Intermediate C2 (230 mg, 0.85 mmol) was dissolved in DCM (6 mL).Trifluoroacetic acid (2 mL) was added and the mixture stirred for 2.5 hat ambient temperature. Evaporation gave Intermediate C containing ˜3 eqof TFA (530 mg, quant).

¹H NMR (400 MHz, d6-DMSO): δ 8.93 (3H, br s), 4.95-4.86 (1H, m), 4.77(2H, s), 2.90 (6H, s), 1.61 (3H, d, J=7.0).

Intermediate D. (S)-1-(5-Dimethylaminomethyl-oxazol-2-yl)-ethylamine TFAsalt

Intermediate D1. ((5)-1-Prop-2-ynylcarbamoyl-ethyl)-carbamic acidtert-butyl ester

A solution of Boc-alanine (1 g, 5.3 mmol) was formed in DCM (40 mL). EDChydrochloride (1.02 g, 5.3 mmol) was added followed by1-hydroxybenzotriazole hydrate (716 mg, 5.3 mmol) and the mixturestirred for 5 mins. Propargyl amine (407 μL, 6.4 mmol) was added and themixture stirred for 27 h at ambient temperature. The mixture waspartitioned between DCM and water. The organic phase was isolated usinga phase separation cartridge and evaporated. Purification by flashcolumn chromatography (40 g Si cartridge) eluting with a gradient of0-100% EtOAc in DCM gave Intermediate D1 as a white solid (1.04 g, 87%).

¹H NMR (400 MHz, CDCl₃): δ 6.39 (1H, br s), 4.89 (1H, br s), 4.19-4.09(1H, m), 4.09-4.00 (2H, m), 2.22 (1H, t, J=2.5 Hz), 1.45 (9H, s), 1.36(3H, d, J=7.1 Hz).

Intermediate D2. [(S)-1-(5-Bromomethyl-oxazol-2-yl)-ethyl]-carbamic acidtert-butyl ester

A solution of Intermediate D1 (500 mg, 2.21 mmol) was formed inchloroform (10 mL). Gold (III) chloride (7 mg, 0.022 mmol) was added andthe mixture was stirred at ambient temperature for 4 hours beforecooling to 0° C. 2,6-Lutadine (260 mg, 2.43 mmol) was added followed bybromine (350 mg, 2.21 mmol) in chloroform (2 mL). The mixture wasallowed to warm to RT overnight. The mixture was diluted with DCM andwashed with an aqueous sodium thiosulphate solution, sat. aqueous sodiumbicarbonate solution, brine and then dried over MgSO₄. Purification byflash column chromatography (24 g Si cartridge) eluting with a gradientof 0-100% EtOAc in cyclohexane gave Intermediate D2 as a colourless oil(320 mg, 47%).

¹H NMR (400 MHz, CDCl₃): δ 6.99 (1H, s), 5.10 (1H, br s), 4.95 (1H, brs), 4.46 (2H, s), 1.54 (3H, d, partially obscured by water), 1.45 (9H,s).

Intermediate D3.[(S)-1-(5-Dimethylaminomethyl-oxazol-2-yl)-ethyl]-carbamic acidtert-butyl ester

Intermediate D2 (320 mg, 1.04 mmol) was dissolved in a solution of 2NNH₃ in THF and stirred at ambient temperature for 1 hour. The mixturewas filtered through celite to remove the white precipitate and thefiltrate was evaporated. Purification by flash column chromatography (12g Si cartridge) eluting with a gradient of 0-100% EtOAc in cyclohexanegave Intermediate D3 as a yellow oil (200 mg, 73%).

¹H NMR (400 MHz, CDCl₃): δ 6.85 (1H, s), 5.17 (1H, br s), 4.93 (1H, brs), 3.50 (2H, s), 2.27 (6H, s), 1.52 (3H, d, J=6.9 Hz), 1.44 (9H, s).

(S)-1-(5-Dimethylaminomethyl-oxazol-2-yl)-ethylamine TFA salt

Intermediate D3 (200 mg, 0.76 mmol) was dissolved in DCM (6 mL).Trifluoroacetic acid (2 mL) was added and the mixture stirred for 2 h atambient temperature. Evaporation gave Intermediate D containing ˜4 eq ofTFA (490 mg, quant).

¹H NMR (400 MHz, d6-DMSO): δ 8.75 (3H, br s), 7.46 (1H, s), 4.71 (1H, brs), 4.50 (2H, s), 2.79 (6H, s), 1.56 (3H, d, J=6.9 Hz).

Intermediate E.(S)-1-(5-Dimethylaminomethyl-oxazol-2-yl)-2-methyl-propylamine TFA salt

Intermediate E was synthesized from Boc-valine using a similar procedureto that for Intermediate D.

¹H NMR (400 MHz, d6-DMSO): δ 8.77 (3H, br s), 7.49 (1H, s), 4.52 (2H,s), 4.46, (1H, s), 2.78 (6H, s), 2.31-2.16 (1H, m), 1.01 (3H, d, J=6.8Hz), 0.87 (3H, d, J=6.8 Hz).

Intermediate F. (S)-1-(5-Dimethylaminomethyl-oxazol-2-yl)-propylamineTFA salt

Intermediate F was synthesized from Boc-(S)-2-amino-butyric acid using asimilar procedure to that for Intermediate D.

¹H NMR (400 MHz, d6-DMSO): δ 8.77 (3H, br s), 7.48 (1H, s), 4.55 (1H, brs), 4.51, (2H, s), 2.79 (6H, s), 2.02-1.90 (2H, m), 0.91 (3H, t, J=7.4Hz).

Intermediate G. 1-(5-Dimethylaminomethyl-oxazol-2-yl)-cyclopropylamineTFA salt

Intermediate G was synthesized from Boc-1-amino-cyclopropanecarboxylicacid using a similar procedure to that for Intermediate D.

¹H NMR (400 MHz, d6-DMSO): δ 9.20 (3H, br s), 7.43 (1H, s), 4.46 (2H,s), 2.77 (6H, s), 1.53 (4H, br s).

Intermediate H.1-(5-Dimethylaminomethyl-oxazol-2-yl)-1-methyl-ethylamine TFA salt

Intermediate H was synthesized from Boc-2-amino-2-methyl-propionic acidusing a similar procedure to that for Intermediate D.

¹H NMR (400 MHz, d6-DMSO): □ 8.88 (3H, br s), 7.47 (1H, s), 4.51 (2H,s), 2.79 (6H, s), 1.66 (6H, s).

Intermediate I. ±1-(4-Dimethylaminomethyl-thiazol-2-yl)-ethylamine

Intermediate I1. 1-(4-Dimethylaminomethyl-thiazol-2-yl)-ethanone

Dimethyl-thiazol-4-ylmethyl-amine (US20150166548) (0.78 g, 5.5 mmol) wasstirred in THF (35 ml) at −78° C. as n-butyllithium (1.6 M in hexanes,4.75 mL, 7.6 mmol) was added over 5 min. keeping the temperature below−60° C. After a further 15 min, N-methoxy-N-methylacetamide (1.13 g, 11mmol) was added. The mixture was allowed to warm gradually to 0° C.,then diluted with water (15 mL) and sat. brine (15 mL). The phases wereseparated and the aqueous was extracted with DCM (15 mL). The combinedorganics were dried (Na₂SO₄) and concentrated. The residue waschromatographed on a 10 g silica column eluting with 0% to 10% MeOH inDCM. The material thus obtained was further purified by SCX-2, loadingin DCM and washing with 20% MeOH in DCM before eluting with 20% of 2Mmethanolic ammonia in DCM to give1-(4-dimethylaminomethyl-thiazol-2-yl)-ethanone as a yellow brown oil(710 mg, 70%).

LCMS (Method U2) Rt=0.21 min, m/z=185.1 [M+H]+.

Intermediate 12. ±1-(4-Dimethylaminomethyl-thiazol-2-yl)-ethanol

1-(4-Dimethylaminomethyl-thiazol-2-yl)-ethanone (impure, 800 mg, ca. 3.7mmol) in MeOH (12 mL) was stirred in an ice bath and treated with sodiumborohydride (168 mg, 4.44 mmol). When gas evolution had ceased it wasallowed to warm slowly to RT. After a further 16 h the mixture wasdiluted with water (30 mL) and extracted with DCM (3×25 mL). The aqueousphase was treated with NaCl and extracted with DCM (2×25 mL). Thecombined organics were dried (Na₂SO₄) and evaporated to give titlecompound as a brown oil (0.58 g, 84%).

LCMS (Method U2) Rt=0.19 min, in/z=187 [M+H]+.

Intermediate 13. ±[2-(1-Azido-ethyl)-thiazol-4-ylmethyl]-dimethyl-amine

±1-(4-Dimethylaminomethyl-thiazol-2-yl)-ethanol (0.58 g, 3.1 mmol) intoluene (3.1 mL) was treated with diphenylphosphoryl azide (1.023 g,3.72 mmol) and DBU (487 mg, 3.2 mmol). The mixture was stirred at RT for3 days then allowed to stand for 65 h. It was then heated at 60° C. for2 h. The mixture was cooled and diluted with DCM (20 mL). The mixturewas washed with sat. Na₂CO₃ solution and the aqueous phase was extractedwith more DCM (20 mL). The combined organic phases were dried (Na₂SO₄)and loaded onto a 10 g silica column and eluted with DCM followed by 5%,10% and 15% MeOH in DCM. The product was re-chromatographed on 5 g and 2g columns to afford the title compound (250 mg, 33%) as a brown oil.

LCMS (Method U2) Rt=0.79 min, m/z=212.1 [M+H]+.

±1-(4-Dimethylaminomethyl-thiazol-2-yl)-ethylamine

±[2-(1-Azido-ethyl)-thiazol-4-ylmethyl]-dimethyl-amine (250 mg, 1 mmol)in THF (5 mL) and water (0.5 mL) was treated with triphenylphosphine(500 mg, 1.9 mmol) and heated at 56° C. for 17 h. The mixture was cooledand filtered through a 2 g SCX-2 cartridge washing with 20% MeOH in DCMand eluting with 20% 2M methanolic ammonia in DCM to give the titlecompound (139 mg, ca. 70%) as a yellow oil.

LCMS (Method U2) Rt=0.22 min, m/z=186.1 [M+H]+.

The following compounds were prepared from the starting materials usinganalogous procedures to that described for Intermediate D1 andIntermediate D.

Inter- mediate Structure Starting materials Data J

N,N-Dimethyl- ethylene-diamine 4-Trans-tert- butoxy-carbonyl-aminocyclo- hexane- carboxylic acid ¹H NMR (400 MHz, d6-DMSO): δ 9.72(1H, br s), 8.11 (1H, m), 7.88 (3H, br s), 3.42-3.37 (2H, m), 3.17-3.10(3H, m), 2.81 (6H, d, J = 5 Hz), 2.13-2.02 (1H, m), 2.02-1.95 (2H, m),1.88-1.80 (2H, m), 1.49-1.22 (4H, m).4-Trans-amino-cyclohexane-carboxylic acid (2-dimethyl-amino-ethyl)-amideTFA salt K

N,N-Dimethyl- ethylene-diamine 4-Cis-tert- butoxy-carbonyl- amino-cyclo-hexane- carboxylic acid ¹H NMR (400 MHz, d6-DMSO): δ 9.65 (1H, br s),8.04 (1H, m), 7.81 (3H, br s), 3.42-3.37 (2H, m), 3.17-3.10 (3H, m),2.81 (6H, d, J = 5 Hz), 2.35-2.29 (1H, m), 1.90-1.81 (2H, m), 1.72-1.50(6H, m). 4-Cis-amino-cyclohexane-carboxylic acid (2-dimethyl-amino-ethyl)-amide TFA salt L

N,N,N′- Trimethyl- ethylene- diamine 4-Trans-tert- butoxy-carbonyl-amino- cyclo-hexane- carboxylic acid ¹H NMR (400 MHz, d6-DMSO):δ 8.20 (3H, br m), 3.66-3.61 (1H, m), 3.21-3.14 (2H, m), 3.05 (3H, s),2.98-2.90 (1H, br m), 2.81-2.72 (8H, m), 2.01-1.94 (2H, m), 1.84- 1.75(2H, m), 1.52-1.31 (4H, m). 4-Trans-amino-cyclohexane-carboxylic acid(2- dimethyl-amino-ethyl)-methyl-amide TFA salt M

(4-Methyl- piperidin-4- yl)-carbamic acid tert-butyl ester Dimethyl-amino-acetic acid LCMS (Method U1) Rt = 0.11 min, m/z = 200 [M + H]+.1-(4-Amino-4-methyl-piperidin-1-yl)-2- dimethylamino-ethanone TFA salt N

(Trans-4- amino- methyl-cyclo- hexyl)- carbamic acid tert-butyl esterDimethyl- amino-acetic acid ¹H NMR (400 MHz, CDCl₃): δ 5.67 (1H, m),4.46 (1H, br s), 3.76-3.69 (1H, m), 3.35 (1H, br s), 3.23-3.17 (1H, m),3.05-3.00 (1H, m), 2.80 (6H, s), 2.05-1.99 (2H, m), 1.83-1.77 (2H, m),1.61 (1H, br s), 1.22- 0.97 (4H, m).N-(Trans-4-amino-cyclohexyl-methyl)-2- dimethylamino-acetamide O

N,N- Dimethyl- ethylene- diamine 3-Trans-tert- butoxy- carbonyl-amino-cyclo-butane- carboxylic acid ¹H NMR (400 MHz, d6-DMSO): δ 8.14 (1H, m),8.03 (3H, br s), 3.81-3.72 (1H, m), 3.41-3.37 (2H, m), 3.15-3.10 (2H,m), 3.07- 2.99 (1H, m), 2.81 (6H, d, J = 4.7 Hz), 2.41- 2.34 (2H, m),2.30-2.22 (2H, m). 3-Trans-amino-cyclobutane-carboxylic acid (2-dimethyl-amino-ethyl)-amide TFA salt P

N,N- Dimethyl- ethylene- diamine 3-Cis-tert- butoxy- carbonyl-amino-cyclo-butane- carboxylic acid ¹H NMR (400 MHz, d6-DMSO): δ 8.16 (1H, m),8.02 (3H, br s), 3.65-3.57 (1H, m), 3.42-3.37 (2H, m), 3.15-3.10 (2H,m), 2.83- 2.76 (7H, m), 2.37-2.29 (2H, m), 2.24-2.15 (2H, m).3-Cis-amino-cyclobutane-carboxylic acid (2- dimethyl-amino-ethyl)-amideTFA salt Q

2-Dimethyl- amino- ethanol 4-Trans-tert- butoxy- carbonyl-amino-cyclo-hexane- carboxylic acid ¹H NMR (400 MHz, CDCl₃): δ 4.16 (2H, t, J= 5.7 Hz), 2.71-2.62 (1H, m), 2.55 (2H, t, J = 5.7 Hz), 2.31-2.23 (7H,m), 2.02-1.88 (4H, m), 1.53-1.43 (2H, m), 1.16-1.05 (2H, m).4-Trans-amino-cyclohexane-carboxylic acid 2- dimethylamino-ethyl ester R

Dimethyl- piperidin-4- yl-amine 4-Trans-tert- butoxy- carbonyl-amino-cyclo-hexane- carboxylic acid ¹H NMR (400 MHz, CDCl₃): δ 4.64 (1H, d, J= 13.4 Hz), 3.94 (1H, d, J = 13.4 Hz), 3.06- 2.98 (1H, m), 2.76-2.67(1H, m), 2.60-2.51 (1H, m), 2.47-2.30 (2H, m), 2.29 (6H, s), 1.96-1.56(8H, m), 1.45-1.31 (2H, m), 1.19- 1.05 (2H, m).(4-Trans-amino-cyclohexyl)-(4-dimethylamino- piperidin-1-yl)-methanone S

1-Methyl- piperidin-4- ylamine 4-Trans-tert- butoxy- carbonyl-amino-cyclo-hexane- carboxylic acid ¹H NMR (400 MHz, d6-DMSO): δ 10.56 (1H, brs), 8.04-7.95 (4H, m), 3.73-3.65 (5H, m), 3.57 (3H, s), 3.52-3.44 (2H,m), 3.38-3.32 (2H, m), 3.26-3.20 (1H, m), 3.09- 2.90 (3H, m), 2.72-2.66(5H, m). 4-Trans-amino-cyclohexanecarboxylic acid (1-methyl-piperidin-4-yl)-amide TFA salt

Example 1.5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid trans-(4-dimethylaminomethyl-cyclohexyl)-amide

A stirred mixture of4-{5-[5-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-imidazol-4-yl]-pyrazol-1-yl}-benzonitrile(Intermediate A, 500 mg, 1.22 mmol) and dichloromethane (15 mL) wastreated with 4-nitrophenyl chloroformate (470 mg, 2.33 mmol).Triethylamine (726 mg, 1.0 mL, 7.12 mmol) was added to the resultantsolution and stirring was continued for 30 minutes. The solution wasadded to trans-4-dimethylaminomethyl-cyclohexylamine trifluoroacetatesalt (1.55 mmol). The mixture was stirred for 1 h then diluted with DCM(15 mL). Water (25 mL) and saturated sodium carbonate solution (5 mL)were added. The phases were partitioned. The aqueous phase was washedwith DCM (2×30 mL). The combined organic phase was dried (sodiumsulfate) and concentrated in vacuo. The residue was part purified usinga 10 g SCX-2 column loading with DCM, washing with 4:1 DCM: methanol andeluting with 4:1 DCM: 2M methanolic ammonia. Concentration of theappropriate fractions gave the crude product. This was further purifiedby filtration through 2×5 g flash NH2 cartridges washing with 4:1 DCM:methanol, then flash chromatography on a 5 g Sill cartridge eluting withDCM, 50:1, 9:1 then 4:1 DCM: methanol. Concentration of the appropriatefractions gave the title compound (425 mg, 0.7 mmol, 59%).

LCMS (Method 3): Rt=3.76 min, m/z 592 [M+H]+

¹H NMR (400 MHz, d6-DMSO): δ 8.18 (1H, d, J=7.7 Hz), 8.02 (1H, s),7.95-7.76 (6H, m), 7.69-7.61 (2H, m), 6.63 (1H, d, J=1.7 Hz), 3.20-3.08(1H, m), 2.06 (6H, s), 1.94 (2H, d, J=7.2 Hz), 1.89 (3H, s), 1.75-1.61(3H, m), 1.47-1.37 (1H, m), 1.37-1.24 (1H, m), 1.16-1.03 (1H, m),0.99-0.71 (3H, m).

The following compounds were prepared by analogous procedures to thatused in Example 1. In the table below where rotameric signals have beenidentified in the NMR spectrum these have been labelled by *.

LC-MS Ex Structure Amine 1H NMR Method 3 2

(1S,2S)-2- Benzyloxy- cyclopentyl- amine ¹H NMR (400 MHz, d6-DMSO): δ8.31 (1H, d, J = 6.9 Hz), 7.93 (1H, m), 7.88-7.74 (6H, m), 7.62 (2H, d,J = 8.5 Hz), 7.34-7.20 (5H, m), 6.62 (1H, d, J = 1.75 Hz), 4.43-4.30(2H, m), 3.79-3.70 (1H, m), 1.87 (3H, s), 1.78-1.10 (7H, m). Rt = 5.83min, m/z = 627.2 [M + H]+, 649.3 (M + Na)+ 3

4-Amino- piperidine-1- carboxylic acid benzyl ester ¹H NMR (400 MHz,d6-DMSO): δ 8.32 (1H, d, J = 7.2 Hz), 8.02 (1H, m), 7.95-7.90 (2H, m),7.90- 7.79 (4H, m), 7.69-7.62 (2H, m), 7.40-7.26 (5H, m), 6.64 (1H, d, J= 1.76 Hz), 5.05 (2H, s), 3.77-3.63 (2H, m), 3.45 (1H, m), 3.08-2.84(2H, m), 1.90 (3H, s), 1.65 (1H, m), 1.41 (1H, m), 1.29 (1H, m), 1.07(1H, m). Rt = 5.50 min, m/z = 670.3 [M + H]+ 4

1-(4-Amino- piperidin-1- yl)-2,2,2- trifluoro- ethanone ¹H NMR (400 MHz,d6-DMSO): δ 8.34 (1H, d, J = 7.2 Hz), 8.01 (1H, m), 7.95-7.90 (2H, m),7.90- 7.78 (4H, m), 7.69-7.63 (2H, m), 6.64 (1H, d, J = 1.75 Hz), 3.98(1H, m), 3.73-3.53 (2H, m), 3.35- 3.22 (1H, m), 3.10-2.97 (1H, m), 1.90(3H, s), 1.77 (1H, m), 1.51 (1H, m), 1.41 (1H, m), 1.26-1.08 (1H, m). Rt= 5.20 min, m/z = 632.3 [M + H]+ 5

(S)-1- Pyridin-4-yl- ethylamine ¹H NMR (400 MHz, CDCl₃): δ 8.88 (1H, t,J = 7 Hz), 8.59-8.53 (1H, m), 8.53-8.49 (1H, m), 7.82- 7.68 (4H, m),7.65 (1H, bs), 7.62-7.52 (3H, m), 7.43-7.37 (1H, m), 7.15-7.12 (1H, m),6.99-6.95 (1H, m), 6.55 (0.5H, d, J = 1.77 Hz)*, 6.53 (0.5H, d, J = 1.77Hz)*, 4.81-4.67 (1H, m), 1.95 (1.5H, s)*, 1.92 (1.5H, s)*, 1.41 (1.5H,d, J = 7 Hz)*, 1.34 (1.5H, d, J = 7 Hz)*. Rt = 3.81 min, m/z = 558.0[M + H]+ 6

(R)-1- Pyridin-4-yl- ethylamine ¹H NMR (400 MHz, CDCl₃): δ 8.88 (1H, t,J = 7 Hz), 8.59-8.53 (1H, m), 8.53-8.49 (1H, m), 7.82- 7.68 (4H, m),7.65 (1H, bs), 7.62-7.52 (3H, m), 7.43-7.37 (1H, m), 7.15-7.12 (1H, m),6.99-6.95 (1H, m), 6.55 (0.5H, d, J = 1.77 Hz)*, 6.53 (0.5H, d, J = 1.77Hz)*, 4.81-4.67 (1H, m), 1.95 (1.5H, s)*, 1.92 (1.5H, s)*, 1.41 (1.5H,d, J = 7 Hz)*, 1.34 (1.5H, d, J = 7 Hz)*. Rt = 3.80 min, m/z = 558.0[M + H]+ 7

3-(4- Methoxy- benzyl)-3- azabicyclo [3.1.0]hex- 6-ylamine ¹H NMR (400MHz, CDCl₃): δ 8.38 (1H, d, J = 3 Hz), 7.80 (1H, d, J = 1.77 Hz),7.76-7.64 (4H, m), 7.62-7.57 (3H, m), 7.49 (1H, dm, J = 7.9 Hz),7.13-7.07 (2H, m), 6.82-6.76 (2H, m), 6.54 (1H, d, J = 1.77 Hz), 3.78(3H, s), 3.50-3.39 (2H, m), 2.97 (2H, dd, J = 8.9 and 2.94 Hz), 2.92(1H, m), 2.34-2.26 (2H, m), 1.83 (3H, s), 1.47-1.41 (1H, m), 1.30-1.24(1H, m). Rt = 3.92 min, m/z = 654.3 [M + H]+ 8

(Trans-4- amino- cyclohexyl)- carbamic acid tert- butyl ester ¹H NMR(400 MHz, CDCl₃): δ 8.36 (1H, d, J = 7.5 Hz), 7.80 (1H, d, J = 1.7 Hz),7.78-7.66 (4H, m), 7.62-7.58 (3H, m), 7.55-7.50 (1H, m), 6.55 (1H, d, J= 1.8 Hz), 4.32-4.32 (1H, bs), 3.48-3.36 (2H, m), 1.98-1.90 (3H, m),1.87 (3H, s), 1.82-1.73 (1H, m), 1.41 (9H, s), 1.30-1.07 (4H, m). Rt =5.52 min, m/z = 650.3 [M + H]+, 672.3 [M + Na]+ 9

N,N- Dimethyl- trans- cyclohexane- 1,4-diamine ¹H NMR (400 MHz, CDCl₃):δ 8.30 (1H, d, J = 7.5 Hz), 7.81 (1H, d, J = 1.8 Hz), 7.78-7.66 (4H, m),7.64-7.57 (3H, m), 7.52 (1H, dm, J = 7.8 Hz), 6.55 (1H, d, J = 1.8 Hz),3.46-3.35 (1H, m), 2.24 (6H, s), 2.14-2.04 (1H, m), 2.00-1.94 (1H, m),1.91-1.75 (3H, m), 1.89 (3H, s), 1.31-0.99 (4H, m). Rt = 3.80 min, m/z =578.3 [M + H]+ 10

(3aS,5R,6aR)- 5-Amino- hexahydro- cyclopenta[c] pyrrole-2- carboxylicacid tert-butyl ester ¹H NMR (400 MHz, CDCl₃): δ 8.52 (1H, d, J = 7.3Hz), 7.81 (1H, d, J = 1.8 Hz), 7.78-7.65 (4H, m), 7.63-7.57 (3H, m),7.55-7.49 (1H, m), 6.55 (1H, d, J = 1.8 Hz), 4.02-3.85 (1H, m),3.47-3.36 (2H, m), 3.21-3.21 (2H, m), 2.60-2.47 (2H, m), 2.32-2.20 (1H,m), 2.20-2.10 (1H, m), 1.88 (3H, s), 1.43 (9H, s), 1.30-1.10 (2H, m). Rt= 5.66 min, m/z = 662.5 [M + H]+, m/z 684.4 [M + Na]+ 11

(S)-2-Amino- 1-(4-methyl- piperazin-1- yl)-propan-1- one ¹H NMR (400MHz, d6-DMSO): δ 9.04 (0.6H, d, J = 6.6 Hz)*, 8.84 (0.4H, d, J = 7.2Hz)*, 8.07-8.00 (1H, m), 7.97-7.78 (6H, m), 7.66 (2H, m), 6.67-6.62 (1H,m)*, 4.46 (0.6H, quintet, J = 6.6 Hz)*, 4.38 (0.4H, quintet, J = 6.8Hz)*, 3.54-3.30 (4H, m), 2.31- 2.16 (4H, s), 2.19 (1.2H, s)*, 2.14(1.8H, s)*, 1.92 (1.8H, s)*, 1.88 (1.2H, s)*, 1.09 (1.2H, d, J = 6.7Hz)*, 0.83 (1.811, d, J = 6.7 Hz)*. Rt = 3.71 min, m/z = 607.4 [M]+ 12

(3aR,5S,6aS)- 5-Amino- hexahydro- cyclopenta- [c]pyrrole-2- carboxylicacid tert- butyl ester ¹H NMR (400 MHz, CDCl₃): δ 8.44 (1H, d, J = 6.8Hz), 7.81 (1H, d, J = 1.8 Hz), 7.77 (1H, dm, J = 8.2 Hz), 7.74-7.66 (3H,m), 7.62 (1H, m), 7.61-7.56 (2H, m), 7.53 (1H, dm, J = 7.8 Hz), 6.56(1H, d, J = 1.8 Hz), 4.11 (1H, ddd, J = 13.0, 13.0, 6.9 Hz), 3.58- 3.37(2H, m), 3.20-2.97 (2H, m), 2.77-2.62 (2H, m), 1.89 (3H, s), 1.83-1.65(3H, m), 1.58-1.48 (1H, m), 1.43 (9H, s). Rt = 5.68 min, m/z = 662.4[M + H]+, 684.4 [M + Na]+ 13

(S)-2-Amino- N-(1-methyl- piperidin-4- yl)-propion- amide ¹H NMR (400MHz, d6-DMSO): δ 8.83 (0.6H, d, J = 6.8 Hz)*, 8.80 (0.4H, d, J = 7.2Hz)*, 8.04 (1H, m), 7.98-7.79 (7H, m), 7.69-7.62 (2H, m), 6.66-6.62 (1H,m), 3.99-3.90 (1H, m), 3.50-3.35 (1H, m), 2.79- 2.61 (2H, m)*, 2.20-2.09(3H, m)*, 2.03-1.88 (2H, m), 1.90 (2H, s)*, 1.87 (1H, s)*, 1.71-1.59(2H, m), 1.42-1.27 (2H, m), 1.11 (1H, d, J = 6.7 Hz)*, 0.88- 0.83 (2H,d, J = 6.7 Hz)*. Rt = 3.68 min, m/z = 621.3 [M + H]+ 14

(S)-1-(4- Dimethyl- aminomethyl- phenyl)- ethylamine ¹H NMR (400 MHz,d6-DMSO): δ 8.71 (0.5H, d, J = 7.5 Hz)*, 8.65 (0.5H, d, J = 7.7 Hz)*,8.03 (1H, m), 7.94 (1H, d, J = 8.2 Hz), 7.92-7.74 (5H, m), 7.68 (1H, d,J = 8.3 Hz), 7.57 (1H, d, J = 8.4 Hz), 7.21- 7.15 (3H, m), 6.95 (1H, d,J = 7.9 Hz), 6.63 (1H, d, J = 6.1 Hz), 4.65-4.50 (1H, m), 3.38 (2H, m),2.14 (3H, s), 2.09 (3H, s), 1.91 (3H, s), 1.32 (1.6H, d, J = 6.8 Hz)*,1.13 (1.4H, d, J = 6.7 Hz)*. Rt = 3.96 min, m/z = 614.3 [M + H]+ 15

1-(4-Amino- piperidin-1- yl)-3- dimethyl- amino- propan-1-one ¹H NMR(400 MHz, d6-DMSO): δ 8.33 (1H, d, J = 7.1 Hz), 8.02 (1H, m), 7.96-7.83(5H, m), 7.82 (1H, t, J = 8.0 Hz), 7.69-7.62 (2H, m), 6.64 (1H, d, J =1.8 Hz), 3.99-3.86 (1H, m), 3.71-3.43 (2H, m), 3.15-3.01 (1H, m),2.87-2.69 (1H, m), 2.41 (4H, s), 2.12 (6H, s), 1.90 (3H, s), 1.77-1.57(1H, m), 1.50- 0.89 (3H, m). Rt = 3.74 min, m/z = 635.4 [M + H]+ 16

Intermed. D ¹H NMR (400 MHz, d6-DMSO): δ 8.99-8.94 (1H, m), 8.04 (1H,s), 7.96-7.80 (6H, m), 7.70-7.60 (2H, m), 6.91 (1H, apparent d J = 7.3Hz), 6.64 (1H, s), 4.72 (1H, quintet J = 7.1 Hz), 3.41 (2H, apparent d J= 9.1 Hz), 2.12 and 2.09 (6H, 2 × s)*, 1.90 and 1.87 (3H, 2 × s)*, 1.33and 1.16 (3H, 2 × d J = 6.7 Hz)*. Rt = 3.70 min, m/z = 605.4 [M + H]+ 17

1-(4-Amino- piperidin-1- yl)-2- dimethyl- amino- ethanone ¹H NMR (400MHz, d6-DMSO): δ 10.32 (0.3H, s)*, 8.30 (0.7H, d J = 7.1 Hz)*, 7.95-7.78(6H, m), 7.74- 7.62 (3H, m), 6.68 (0.3H, d J = 1.8 Hz)*, 6.61 (0.7H, d J= 1.8 Hz)*, 3.90-3.74 (2H, m), 3.58-3.50 (1H, m), 3.08-3.0 (peaksobscured by water), 2.18 and 2.17 (6H, 2s)*, 1.86 (2H, s)*, 1.70 (1H,s)*, 1.69-1.40 (2H, m), 1.30-1.10 (1H, m). Rt = 3.70 min, m/z = 621.3[M + H]+ 18

(S)-2-Amino- N-methyl-N- (1-methyl- piperidin- 4-ylmethyl)-propion-amide ¹H NMR (400 MHz, d6-DMSO at 80° C.): δ 8.86 (1H, br s),7.92 (1H, s), 7.88-7.78 (6H, m), 7.65 (2H, d J = 8.8 Hz),6.61 (1H, d J =1.7 Hz), 4.45 (1H, quintet J = 6.7 Hz), 3.22 (1H,br s), 3.10-3.00 (1H,peaks partially obscured by water), 2.92-2.76 (3H, m), 2.74-2.62 (2H,m), 2.12 (3H, br s), 1.88-1.74 (5H, m), 1.56-1.38 (3H, m), 1.22-0.88(5H, m) Rt = 3.74 min, m/z = 649.5 [M + H]+ 19

(S)-2-Amino- 1-(4- dimethyl- amino- piperidin-1- yl)-propan-1- one ¹HNMR (400 MHz, d6-DMSO): δ 9.10-8.80 (1H, 4 × d)*, 8.05-8.00 (1H, m),7.95-7.75 (6H, m), 7.72- 7.62 (2H, m), 6.66-6.62 (1H, m), 4.52-4.36 (1H,m), 4.32-4.16 (1H, m), 3.76-3.60 (1H, m), 3.05-2.80 (1H, m), 2.70-2.55(1H, m), 2.35-2.21 (1H, m), 2.20- 2.16 (6H, m), 1.95-1.84 (3H, m),1.76-1.64 (2.4H, m)*, 1.35-1.05 (4H, m), 0.87-0.78 (1.6H, m)*. Rt = 3.70min, m/z = 635.4 [M]+ 20

(S)-2-Amino- N- (2-dimethyl- amino-ethyl)- N-methyl- propion-amide ¹HNMR (400 MHz, d6-DMSO): δ 8.85 (1H, br s), 7.94-7.90 (1H, m), 7.89-7.77(5H, m), 7.75-7.61 (3H, m), 6.61 (1H, d J = 1.8 Hz), 4.50-4.40 (1H, m),3.50-3.20 (2H, m), 2.87 (3H, br s), 2.32 (2H, t J = 6.6 Hz), 2.12 (6H,s)1.85 (3H, br s), 1.20-0.85 (3H, br m). Rt = 3.67 min, m/z = 609.4 [M +H]+ 21

Intermed. E ¹H NMR (400 MHz, d6-DMSO): δ 9.09 (d, 0.6H, J = 8.75 Hz)*,8.95 (d, 0.4H, J = 8.44 Hz)*, 8.07 (s, 1H), 7.96-7.74 (m, 5H), 7.66 (d,1H, J = 8.65 Hz), 7.58 (d, 1H, J = 8.55 Hz), 6.92 (s, 1H), 6.67-6.61 (m,1H), 4.54-4.44 (m, 1H), 3.50-3.39 (m, 2H), 2.15- 2.05 (m, 6H), 1.97-1.81(m, 4H), 0.76 (d, 2H, apparent dd, J = 6.71), 0.62 (d, 2H, J = 6.76 Hz),0.55 (d, 2H, J = 6.72 Hz). Rt = 3.89 min, m/z = 633.4 [M + H]+ 22

Intermed. F ¹H NMR (400 MHz, d6-DMSO): δ 9.01 (d, 0.6H, J = 7.74 Hz)*,8.94 (d, 0.4H, J = 7.72 Hz)*, 8.06 (s, 1H), 7.97-7.78 (m, 5H), 7.67 (d,1H, J = 8.58 Hz), 7.61 (d, 1H, J = 8.47 Hz), 6.92 (s, 1H), 6.65 (d, 1H,J = 1.75 Hz), 4.65-4.56 (m, 1H), 3.48-3.38 (m, 2H), 2.15-2.04 (m, 6H),1.96-1.84 (m, 3H), 1.83-1.63 (m, 1H), 1.63-1.44 (m, 1H), 0.72 (t, 1H, J= 7.17 Hz), 0.52 (t, 2H, J = 7.26 Hz). Rt = 3.78 min, m/z = 619.3 [M +H]+ 23

Intermed. G ¹H NMR (400 MHz, d6-DMSO): δ 9.09 (s, 1H), 8.04 (s, 1H),7.95-7.82 (m, 6H), 7.64 (d, 2H, J = 8.83 Hz), 6.80 (s, 1H), 6.64 (d, 1H,J = 1.76), 3.32 (s, 2H), 2.07 (s, 6H), 1.89 (s, 3H), 1.32-1.21 (m, 2H),1.20-1.09 (m, 1H), 0.77-0.65 (m, 1H). Rt = 3.66 min, m/z = 617.3 [M +H]+ 24

Intermed. H ¹H NMR (400 MHz, d6-DMSO): δ 9.12 (s, 1H), 8.06 (br s, 1H),7.94-7.80 (m, 6H), 7.61 (d, 2H, J = 8.32 Hz), 6.83 (s, 1H), 6.60 (d, 1H,J = 1.75 Hz), 3.37 (s, 2H), 2.06 (s, 6H), 1.90 (s, 3H), 1.35 (d, 6H, J =7.56 Hz). Rt = 3.74 min, m/z = 619.3 [M + H]+ 25

Intermed. M ¹H NMR (400 MHz, d6-DMSO): δ 8.47 (d, 1H, J = 23.78 Hz),8.04 (s, 1H), 7.96-7.79 (m, 5H), 7.64 (d, 2H, J = 8.58 Hz), 6.64 (d, 1H,J = 1.69 Hz), 5.76 (s, 1H), 3.88 (dd, 1H, J = 42.07, 13.06 Hz), 3.75-3.55 (m, 1H), 3.31-3.25 (m, 1H), 3.16-2.87 (m, 2H), 2.65 (q, 1H, J =13.37 Hz), 2.13 (d, 6H, J = 13.29 Hz), 1.95 (s, 3H), 1.83-1.66 (m, 1H),1.66-1.53 (m, 1H), 1.42-1.13 (m, 2H), 1.01 (s, 3H). Rt = 3.79 min, m/z =635.3 [M + H]+ 26

N-(Trans-4- amino- cyclohexyl)-2- dimethyl- amino- acetamide ¹H NMR (400MHz, d6-DMSO): δ 8.20 (1H, d, J = 7.48 Hz), 8.01 (1H, s), 7.94-7.78 (6H,m), 7.66 (2H, d, J = 8.78 Hz), 7.45 (1H, d, J = 8.37 Hz), 6.63 (1H, d, J= 1.75 Hz), 3.59-3.42 (1H, m), 3.23-3.08 (1H, m), 2.79 (2H, s), 2.16(6H, s), 1.88 (3H, s), 1.77-1.56 (3H, m), 1.46-1.34 (1H, m), 1.33-1.13(3H, m), 1.11-0.96 (1H, m). Rt = 3.72 min, m/z = 635.3 [M + H]+ 27

Intermed. N ¹H NMR (400 MHz, d6-DMSO): δ 8.17 (1H, d, J = 7.51 Hz), 8.01(1H, s), 7.93-7.78 (6H, m), 7.70- 7.62 (3H, m), 6.63 (1H, d, J = 1.76Hz), 3.17-3.06 (1H, m), 2.89 (2H, t, J = 6.38 Hz), 2.81 (2H, s), 2.17(6H, s), 1.89 (3H, s), 1.75-1.65 (1H, m), 1.58 (2H, br s), 1.46-1.26(2H, m), 1.15-1.00 (1H, m), 0.95-0.76 (3H, m). Rt = 3.85 min, m/z =649.4 [M + H]+ 28

(S)-2-Amino- N-methyl-N- (1-methyl- piperidin- 4-yl)-propion- amide ¹HNMR (400 MHz, d6-DMSO): δ 9.08 (0.2H, d, J = 6.64 Hz)*, 9.03 (0.3H, d, J= 6.66 Hz)*, 8.90 (0.2H, d, J = 7.41 Hz)*, 8.82 (0.3H, d, J = 7.37 Hz)*,8.03 (1H, s), 7.97-7.79 (7H, m), 7.71-7.60 (2H, m), 6.63 (1H, s),4.50-4.31 (1H, m), 4.15- 4.02 (1H, m), 3.31 (3H, s), 2.87-2.62 (5H, m),2.19-2.08 (3H, m), 2.00-1.44 (8H, m), 1.42-1.21 (2H, m), 1.16-1.05(1.5H, m)*, 0.82 (1.5H, d, J = 6.62 Hz)*. Rt = 3.64 min, m/z = 635.3[M + H]+

Example 29.(Trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-trimethyl-ammoniumbenzene sulfonate

A solution of Example 1 (120 mg, 0.2 mmol) in THF (0.25 mL) was treatedwith methyl benzenesulfonate (38 mg, 30 uL, 0.22 mmol). The mixture wasstirred for 3 days at ambient temperature. The resultant white mass wasdiluted with diethyl ether (4 mL) and stirred for 30 min. The solid wasrecovered by filtration and freeze-dried from acetonitrile/water toafford the title compound (150 mg, 0.19 mmol, 95%). LCMS (Method 3):Rt=3.90 min, m/z 606.4 [M]+

¹H NMR (400 MHz, CDCl₃): δ 8.32 (1H, d, J=7.4 Hz), 7.87-7.82 (2H, m),7.81 (11-1, d, J=1.8 Hz), 7.78-7.74 (1H, m), 7.74-7.67 (3H, m), 7.63(1H, m), 7.61-7.56 (2H, m), 7.54 (1H, dm, J=7.8 Hz), 7.37-7.29 (3H, m),6.55 (1H, d, J=1.8 Hz), 3.39-3.20 (3H, m), 3.30 (9H, s), 1.95-1.69 (5H,m), 1.89 (3H, s), 1.27-1.06 (4H, m).

Example 30.Benzyl-(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-dimethyl-ammoniumbromide

A solution of Example 1 (120 mg, 0.2 mmol) in THF (0.25 mL) was treatedwith benzyl bromide (38 mg, 27 uL, 0.22 mmol). The mixture was stirredfor 3 days at ambient temperature then diluted with diethyl ether (3 mL)causing a white solid to form. The mixture was stirred for 30 min. thenthe solid was recovered by filtration. It was freeze-dried fromacetonitrile/water to afford the title compound (140 mg, 0.18 mmol,90%).

LCMS (Method 3): Rt=4.25 min, m/z 682.5 [M]+

¹H NMR (400 MHz, CDCl₃): δ 8.34 (1H, d, J=7.3 Hz), 7.81 (1H, d, J=1.8Hz), 7.78-7.67 (4H, m), 7.67-7.56 (5H, m), 7.54 (1H, dm, J=8.1 Hz),7.50-7.38 (3H, m), 6.55 (1H, d, J=1.8 Hz), 5.10-5.00 (2H, m), 3.62-3.55(1H, m), 3.46-3.30 (2H, m), 3.27 (3H, s), 3.24 (3H, s), 2.07-1.83 (4H,m), 1.89 (3H, s), 1.79-1.69 (1H, m), 1.34-1.14 (4H, m).

Example 31.(Trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-ethyl-dimethyl-ammoniumbenzene sulfonate

A solution of Example 1 (120 mg, 0.2 mmol) in THF (0.25 mL) was treatedwith ethyl benzenesulfonate (38 mg, 30 uL, 0.22 mmol). The mixture wasstirred for 3 days at ambient temperature then at 50° C. for a further 3days giving a thick white mass. The mixture was then cooled to ambienttemperature and triturated with diethyl ether (3 mL). The residue wasfreeze-dried from acetonitrile/water to afford the title compound; (140mg,

0.18 mmol, 90%).

LCMS (Method 3): Rt=3.93 min, m/z 620.4 [M]+

¹H NMR (400 MHz, CDCl₃): δ 8.32 (111, d, J=7.3 Hz), 7.88-7.83 (2H, m),7.81 (1H, d, J=1.8 Hz), 7.78-7.66 (4H, m), 7.64-7.56 (3H, m), 7.56-7.51(1H, m), 7.36-7.30 (3H, m), 6.55 (1H, d, J=1.8 Hz), 3.60-3.51 (2H, m),3.42-3.14 (4H, m), 3.22 (3H, s), 3.21 (3H, s), 1.95-1.69 (4H, m), 1.89(3H, s), 1.32 (3H, t, J=7.0 Hz), 1.28-1.02 (4H, m).

The following compounds were prepared by analogous procedures to thatused in Examples 1, 29, 30 and 31. In the table below where rotamericsignals have been identified in the NMR spectrum these have beenlabelled by *.

Quat. LC-MS Ex Structure Amine Method 1H NMR Method 3 32

1-Methyl- piperidin-4- ylamine Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 8.36(1H, d, J = 7.7 Hz), 8.01 (1H, m), 7.94-7.80 (6H, m), 7.70-7.63 (2H, m),7.61-7.56 (2H, m), 7.35-7.25 (3H, m), 6.65 (1H, d, J = 1.76 Hz), 3.54(1H, m), 3.38-3.23 (4H, m), 3.04 (6H, s), 1.97-1.83 (1H, m), 1.92 (3H,s), 1.82-1.64 (2H, m), 1.54- 1.43 (1H, m). Rt = 3.55 min, no [M]+observed, m/z = 408.2 [M-side- chain]- 33

(R)-1-Methyl- pyrrolidin-3- ylamine Ex 29 ¹H NMR (400 MHz, CDCl₃): δ9.03-8.93 (1H, m)*, 7.88-7.81 (2H, m), 7.79 (1H, bs), 7.76- 7.69 (3H,m), 7.68-7.57 (4H, m), 7.53 (1H, tm, J = 7 Hz), 7.34- 7.26 (3H, m),6.61-6.53 (1H, m)*, 4.64-4.51 (1H, m), 4.01-3.83 (2H, m), 3.82-3.61 (2H,m), 3.34 (3H, s), 3.25 (3H, s), 2.62-2.48 (1H, m), 2.16-2.04 (1H, m),1.84-1.75 (3H, m)*. Rt = 3.53 min, m/z = 550.2 [M]+ 34

(S)-1-Methyl- pyrrolidin-3- ylamine Ex 29 ¹H NMR (400 MHz, CDCl₃): δ9.03-8.93 (1H, m)*, 7.88-7.81 (2H, m), 7.79 (1H, bs), 7.76- 7.69 (3H,m), 7.68-7.57 (4H, m), 7.53 (1H, tm, J = 7 Hz), 7.34- 7.26 (3H, m),6.61-6.53 (1H, m)*, 4.64-4.51 (1H, m), 4.01-3.83 (2H, m), 3.82-3.61 (2H,m), 3.34 (3H, s), 3.25 (3H, s), 2.62-2.48 (1H, m), 2.16-2.04 (1H, m),1.84-1.75 (3H, m)*. Rt = 3.53 min, m/z = 550.3 [M]+ 35

1-(1-Methyl- piperidin-4- yl)- ethylamine Ex 29 ¹H NMR (400 MHz,d6-DMSO): δ 8.35-8.28 (0.5H, m)*, 8.15- 8.08 (0.5H, m)*, 8.02 (1H, m),7.98-7.88 (3H, m), 7.88-7.80 (3H, m), 7.69-7.63 (2H, m), 7.61- 7.56 (2H,m), 7.34-4.26 (3H, m), 6.64 (1H, d, J = 1.75 Hz), 3.48-3.29 (2H, m),3.23-3.12 (2H, m), 3.12-2.88 (6H, m), 1.99-1.89 (3H, m), 1.72-1.55 (2H,m), 1.55-1.35 (3H, m), 1.29-1.19 (1H, m), 0.99 (1.5H, d, J = 6 Hz)*,0.78 (1.5H, d, J = .6 Hz)*. Rt = 3.73 min, m/z = 592.3 [M]+ 36

(1S,3R,5R)-8- Methyl-8-aza- bicyclo[3.2.1] oct-3-ylamine Ex 29 ¹H NMR(400 MHz, CDCl₃): δ 9.10 (1H, d, J = 6 Hz), 7.87-7.80 (3H, m), 7.79-7.66(4H, m), 7.64- 7.53 (4H, m), 7.35-7.29 (3H, m), 6.57 (1H, d, J = 1.76Hz), 4.14 (1H, m), 4.00 (1H, m), 3.92- 3.83 (1H, m), 3.32 (3H, s), 3.24(3H, s), 2.68-2.49 (2H, m), 2.45-2.33 (2H, m), 2.24-2.03 (2H, m), 1.91(3H, s), 1.84-1.76 (1H, m), 1.64-1.56 (1H, m). Rt = 3.86 min, m/z =590.3 [M]+ 37

(3aS,5R,6aR)- 2-Methyl- octahydro- cyclopenta[c] pyrrol-5- ylamine Ex 29¹H NMR (400 MHz, CDCl₃): δ 8.63 (1H, d, J = 6.8 Hz), 7.89- 7.82 (2H, m),7.80 (1H, d, J = 1.8 Hz), 7.78-7.71 (3H, m), 7.69- 7.53 (5H, m),7.30-7.27 (3H, m), 6.57 (1H, d, J = 1.8 Hz), 4.09- 3.99 (1H, m),3.98-3.89 (2H, m), 3.55-3.45 (2H, m), 3.44 (3H, s), 3.17 (3H, s),3.04-2.90 (2H, m), 2.17-1.98 (2H, m), 1.86 (3H, s), 1.67-1.55 (2H, m).Rt = 3.75 min, m/z = 590.4 [M]+ 38

See Ex 5 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 9.01-8.95 (0.5H, m)*, 8.92-8.81 (2.5H, m)*, 8.05-7.77 (9H, m), 7.71-7.64 (1H, m), 7.61- 7.58 (2H,m), 7.58-7.51 (1H, m), 7.35-7.25 (3H, m), 6.66-6.62 (0.5H, bs)*,6.66-6.59 (0.5H, bs)*, 4.87-4.76 (1H, m), 4.35 (1.5H, s)*, 4.25 (1.5H,s)*, 1.91 (3H, s), 1.37 (1.5H, d, J = 6.4 Hz)*, 1.31 (1.5H, d, J = 6.4Hz)*. Rt = 3.77 min, m/z = 572.2 [M]+ 39

(1S,3S,5R)-8- Methyl-8-aza- bicyclo[3.2.1] oct-3-ylamine Ex 29 ¹H NMR(400 MHz, CDCl₃): δ 8.71 (1H, d, J = 7.5 Hz), 7.89- 7.83 (2H, m), 7.82(1H, d, J = 1.8 Hz), 7.77-7.71 (3H, m), 7.70- 7.59 (4H, m), 7.57 (1H,dm, J = 7.8 Hz), 7.35-7.29 (3H, m), 6.56 (1H, d, J = 1.8 Hz), 4.18 (1H,bs), 4.03 (1H, bs), 3.99-3.85 (1H, m), 3.46 (3H, s), 3.23 (3H, s),2.40-2.29 (2H, m), 2.29- 2.18 (2H, m), 1.99-1.88 (2H, m), 1.83 (3H, s),1.83-1.74 (2H, m). Rt = 3.81 min, m/z = 590.3 [M]+ 40

1-Ethyl- piperidin-4- ylamine Ex 31 ¹H NMR (400 MHz, CDCl₃): δ 8.72 (1H,d, J = 6.7 Hz), 7.91- 7.83 (2H, m), 7.80 (1H, d, J = 1.8 Hz), 7.79-7.74(2H, m), 7.74- 7.69 (1H, m), 7.69-7.58 (5H, m), 7.33-7.27 (3H, m), 6.59(1H, d, J = 1.8 Hz), 3.92-3.83 (1H, m), 3.63-3.52 (2H, m), 3.53-3.34(6H, m), 2.02-1.88 (3H, m), 1.86 (3H, s), 1.83-1.77 (1H, m), 1.27-1.19(6H, m). Rt = 3.80 min, m/z = 592.3 [M]+ 41

See Ex 9 Ex 29 ¹H NMR (400 MHz, CDCl₃): δ 8.37 (1H, d, J = 7.3 Hz),7.88- 7.82 (2H, m), 7.81 (1H, d, J = 1.7 Hz), 7.78-7.66 (4H, m), 7.63-7.57 (3H, m), 7.57-7.52 (1H, m), 7.36-7.28 (3H, m), 6.55 (1H, d, J = 1.7Hz), 3.68-3.52 (1H, m), 3.45-3.30 (1H, m), 3.19 (9H, s), 2.26-2.11 (2H,m), 2.08-1.98 (1H, m), 1.87 (3H, s), 1.86- 1.82 (1H, m), 1.49-1.17 (4H,m). Rt = 3.82 min, m/z = 592.4 [M]+ 42

See Ex 5 Ex 31 ¹H NMR (400 MHz, CDCl₃): δ 9.27 (0.4H, d, J = 6.7 Hz)*,9.25-9.19 (0.6H, m)*, 9.08-9.00 (2H, m), 7.92-7.82 (3H, m), 7.81-7.52(10H, m), 7.34-7.29 (3H, m), 6.69 (0.4H, d, J = 1.7 Hz)*, 6.66 (0.2H, d,J = 1.7 Hz)*, 6.56 (0.4H, d, J = 1.7 Hz)*, 4.99-4.60 (3H, m), 1.87-1.84(3H, m)*, 1.61 (1.3H, t, J = 7.3 Hz)*; 1.55-1.48 (1.7H, m)*, 1.48-1.40(3H, m). Rt = 3.86 min, m/z = 586.3 [M]+ 43

See Ex 9 Ex 30 ¹H NMR (400 MHz, CDCl₃): δ 8.45 (1H, d, J = 7.3 Hz), 7.81(1H, d, J = 1.77 Hz), 7.78-7.67 (4H, m), 7.64-7.53 (6H, m), 7.50-7.40(3H, m), 6.57 (1H, d, J = 1.77 Hz), 5.00-4.89 (2H, m), 3.85 (1H, tm, J =12 Hz), 3.54- 3.44 (1H, m), 3.16 (3H, s), 3.14 (3H, s), 2.46-2.28 (2H,m), 2.21- 2.11 (1H, m), 2.04-1.93 (1H, m), 1.88 (3H, s), 1.74-1.62 (2H,m), 1.45-1.19 (2H, m). Rt = 4.17 min, m/z = 668.4 [M]+ 44

See Ex 9 Ex 31 ¹H NMR (400 MHz, CDCl₃): δ 8.40 (1H, d, J = 7.3 Hz),7.88- 7.84 (2H, m), 7.81 (1H, d, J = 1.8 Hz), 7.78-7.67 (4H, m), 7.63-7.57 (3H, m), 7.55 (1H, dm, J = 7.6 Hz), 7.36-7.28 (3H, m), 6.56 (1H, d,J = 1.8 Hz), 3.57- 3.32 (4H, m), 3.12 (3H, s), 3.10 (3H, s), 2.24-2.01(3H, m), 1.96- 1.84 (1H, m), 1.88 (3H, s), 1.58-1.19 (4H, m), 1.33 (3H,t, J = 6.8 Hz). Rt = 3.86 min, m/z = 606.4 [M]+ 45

N,N- Dimethyl-cis- cyclohexane- 1,4-diamine Ex 29 ¹H NMR (400 MHz,CDCl₃): δ 8.61 (1H, d, J = 6.5 Hz), 7.86- 7.82 (2H, m), 7.81 (1H, d, J =1.8 Hz), 7.78-7.73 (3H, m), 7.68 (1H, tm, J = 7.8 Hz), 7.64-7.55 (4H,m), 7.33-7.28 (3H, m), 6.56 (1H, d, J = 1.8 Hz), 3.82 (1H, tm, J = 11.6Hz), 3.76-3.69 (1H, m), 3.22-3.20 (9H, s), 2.13-1.98 (2H, m), 1.94 (3H,s), 1.93- 1.84 (1H, m), 1.69-1.44 (2H, m), 1.52-1.39 (1H, m), 1.36-1.19(2H, m). Rt = 3.70 min, m/z = 592.4 [M]+ 46

N,N- Dimethyl-cis- cyclohexane- 1,4-diamine Ex 30 ¹H NMR (400 MHz,CDCl₃): δ 8.66 (1H, d, J = 6.2 Hz), 7.83 (1H, d, J = 1.77 Hz), 7.81-7.75(3H, m), 7.72 (1H, tm, J = 7.5 Hz), 7.67-7.58 (6H, m), 7.49- 7.42 (3H,m), 6.59 (1H, d, J = 1.77 Hz), 4.86 (2H, s), 4.34-4.22 (1H, m),3.83-3.77 (1H, m), 3.13 (3H, s), 3.10 (3H, s), 2.35-2.24 (1H, m),2.21-2.11 (1H, m), 2.04-1.92 (1H, m), 1.98 (3H, s), 1.88-1.77 (1H, m),1.76-1.56 (3H, m), 1.51-1.39 (1H, m). Rt = 4.10 min, m/z = 668.5 [M]+ 47

1-Methyl-1- pyridin-4-yl- ethylamine Ex 29 ¹H NMR (400 MHz, CDCl₃): δ9.35 (1H, s), 8.88 (2H, d, J = 6.7 Hz), 7.89-7.82 (2H, m), 7.82- 7.70(5H, m), 7.70-7.64 (2H, m), 7.63 (1H, d, J = 1.75 Hz), 7.61- 7.56 (1H,m), 7.55-7.49 (2H, m), 7.33-7.29 (3H, m), 6.56 (1H, d, J = 1.75 Hz),4.28 (3H, s), 1.91 (3H, s), 1.46 (3H, s), 1.42 (3H, s). Rt = 3.88 min,m/z = 586.4 [M]+ 48

N,N- Dimethyl-cis- cyclohexane- 1,4-diamine Ex 31 ¹H NMR (400 MHz,CDCl₃): δ 8.61 (1H, d, J = 6.3 Hz), 7.88- 7.83 (2H, m), 7.82 (1H, d, J =1.76 Hz), 7.79-7.73 (3H, m), 7.68 (1H, tm, J = 7.8 Hz), 7.65-7.57 (4H,m), 7.33-7.28 (3H, m), 6.57 (1H, d, J = 1.76 Hz), 3.79-3.64 (2H, m),3.48 (2H, q, J = 7 Hz), 3.13 (3H, s), 3.10 (3H, s), 2.12- 1.87 (4H, m),1.95 (3H, s), 1.76-1.50 (3H, m), 1.44-1.30 (1H, m), 1.36 (3H, t, J = 7Hz). Rt = 3.76 min, m/z = 606.4 [M]+ 49

See Ex 11 Ex 30 ¹H NMR (400 MHz, d6-DMSO): δ 9.12-8.90 (1H, m)*, 8.09-7.98 (1H, m)*, 7.97-7.81 (6H, m), 7.73-7.63 (2H, m), 7.60- 7.46 (5H, m),6.67-6.64 (1H, m), 4.72-4.46 (3H, m), 4.23-4.05 (1H, m), 4.03-3.89 (1H,m), 3.78-3.62 (1H, m), 3.61-3.29 (5H, m), 3.06-2.95 (3H, m), 1.98- 1.82(3H, m), 1.22-1.11 (1H, m)*, 0.95-0.80 (2H, m)*. Rt = 4.03 min, m/z =697.5 [M]+ 50

See Ex 11 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 9.05 (0.6H, d, J = 6.5Hz)*, 8.96 (0.4H, d, J = 6.9 Hz)*, 8.07- 8.00 (1H, m)*, 7.97-7.79 (6H,m), 7.72-7.65 (2H, m), 7.62-7.56 (2H, m), 7.35-7.26 (3H, m), 6.66-6.64(1H, m)*, 4.59-4.48 (1H, m), 3.88-3.64 (4H, m), 3.45-3.27 (4H, m),3.20-3.06 (6H, m)*, 1.94 (1.9H, s)*, 1.86 (1.1H, s)*, 1.14 (1H, d, J =7.2 Hz)*, 0.86 (2H, d, J = 6.7 Hz)*. Rt = 3.72 min, m/z = 621.4 [M]+ 51

7-Methyl-7- aza- spiro[3.5]- non-2- ylamine Ex 29 ¹H NMR (400 MHz,d6-DMSO): δ 8.42 (1H, d, J = 7.4 Hz), 8.00 (1H, s), 7.95-7.79 (6H, m),7.69-7.63 (2H, m), 7.61-7.56 (2H, m), 7.33-7.28 (3H, m), 6.64 (1H, d, J= 1.8 Hz), 3.88 (1H, tdt, J = 7.8, 7.8, 7.9 Hz), 3.27- 3.12 (4H, m),3.02 (6H, s), 2.18- 1.97 (2H, m), 1.90 (3H, s), 1.85- 1.64 (5H, m),1.50-1.42 (1H, m). Rt = 3.85 min, m/z = 604.4 [M]+ 52

See Ex 6 Ex 29 ¹H NMR (400 MHz, CDCl₃): δ 9.26 (0.4H, d, J = 6.9 Hz)*,9.22 (0.6H, d, J = 6.0 Hz)*, 8.94 (1H, d, J = 6.4 Hz)*, 8.91 (1H, d, J =6.2 Hz)*, 7.89-7.78 (3H, m), 7.78-7.68 (4H, m), 7.68-7.61 (3H, m),7.61-7.51 (3H, m), 7.34- 7.28 (3H, m), 6.68 (0.5H, d, J = 1.7 Hz)*, 6.61(0.1H, d, J = 1.7 Hz)*, 6.55 (0.4H, d, J = 1.7 Hz)*, 4.91 (0.4H, td, J =14.0, 7.0 Hz)*, 4.82 (0.6H, td, J = 13.8, 6.9 Hz)*, 4.45 (1.2H, s)*,4.35 (0.3H, s)*, 4.33 (1.5H, s)*, 1.87-1.83 (3H, m), 1.44-1.39 (3H, m).Rt = 3.76 min, m/z = 572.3 [M]+ 53

4-Dimethyl- aminomethyl- cis- cyclohexyl- amine Ex 29 ¹H NMR (400 MHz,CDCl₃): δ 8.52 (1H, d, J = 6.5 Hz), 7.89- 7.82 (2H, m), 7.81 (1H, d, J =1.8 Hz), 7.78-7.72 (3H, m), 7.68 (1H, t, J = 8.0 Hz), 7.64 (1H, m),7.62-7.56 (3H, m), 7.34-7.27 (3H, m), 6.56 (1H, d, J = 1.8 Hz),3.69-3.62 (1H, m), 3.39 (1H, dd, J = 13.4, 3.6 Hz), 3.30 (9H, s), 3.21(1H, dd, J = 13.4, 4.8 Hz), 1.94 (3H, s), 1.94-1.84 (1H, m), 1.70-1.52(4H, m), 1.45- 1.20 (3H, m), 1.13-1.04 (1H, m). Rt = 3.83 min, m/z =606.4 [M]+ 54

4-Dimethyl- aminomethyl- cis- cyclohexyl- amine Ex 30 ¹H NMR (400 MHz,CDCl₃): δ 8.53 (1H, d, J = 6.3 Hz), 7.81 (1H, d, J = 1.8 Hz), 7.79-7.72(3H, m), 7.71 (1H, t, J = 7.8 Hz), 7.67-7.58 (6H, m), 7.51-7.39 (3H, m),6.57 (1H, d, J = 1.8 Hz), 5.06-4.95 (2H, m), 3.77-3.68 (1H, m),3.68-3.60 (1H, m), 3.34- 3.25 (1H, m), 3.28 (3H, s), 3.27 (3H, s),2.29-2.18 (1H, m), 1.96 (3H, s), 1.82-1.64 (4H, m), 1.62-1.52 (1H, m),1.50-1.41 (1H, m), 1.41-1.27 (1H, m), 1.18-1.05 (1H, m). Rt = 4.21 min,m/z = 682.4 [M]+ 55

4-Dimethyl- aminomethyl- cis- cyclohexyl- amine Ex 31 ¹H NMR (400 MHz,CDCl₃): δ 8.53 (1H, d, J = 6.4 Hz), 7.89- 7.83 (2H, m), 7.81 (1H, d, J =1.8 Hz), 7.78-7.71 (3H, m), 7.69 (1H, tm, J = 7.8 Hz), 7.64 (1H, m),7.62-7.56 (3H, m), 7.34-7.28 (3H, m), 6.56 (1H, d, J = 1.8 Hz),3.72-3.64 (1H, m), 3.63-3.51 (2H, m), 3.32 (1H, dd, J = 13.6, 3.7 Hz),3.23 (3H, s), 3.21 (3H, s), 3.16 (1H, dd, J = 13.6, 4.9 Hz), 2.01-1.89(1H, m), 1.96 (3H, s), 1.74-1.54 (3H, m), 1.52-1.20 (4H, m), 1.33 (3H,t, J = 7.2 Hz), 1.13-1.04 (1H, m). Rt = 3.88 min, m/z = 620.4 [M]+ 56

(3aR,5S, 6aS)-2- Methyl- octahydro- cyclopenta- [c]pyrrol-5- ylamine Ex29 ¹H NMR (400 MHz, CDCl₃): δ 8.55 (1H, d, J = 6.5 Hz), 7.87- 7.82 (2H,m), 7.81 (1H, d, J = 1.8 Hz), 7.77 (1H, dm, J = 7.8 Hz), 7.74-7.66 (3H,m), 7.61 (1H, m), 7.60-7.56 (2H, m), 7.53 (1H, dm, J = 8.4 Hz),7.36-7.29 (3H, m), 6.56 (1H, d, J = 1.8 Hz), 4.21-4.13 (1H, m),4.08-3.99 (1H, m), 3.98-3.90 (1H, m), 3.42 (3H, s), 3.20 (3H, s),3.162.95 (4H, m), 1.88 (3H, s), 1.88-1.83 (1H, m), 1.83-1.75 (1H, m),1.70- 1.60 (1H, m), 1.58-1.46 (1H, m). Rt = 3.76 min, m/z = 590.4 [M]+57

See Ex 13 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 8.82 (1H, d, J = 6.9 Hz),8.12-7.99 (2H, m), 7.96-7.79 (6H, m), 7.69-7.63 (2H, m), 7.61- 7.58 (2H,m), 7.32-7.29 (3H, m), 6.65 (1H, d, J = 1.7 Hz), 4.02- 3.89 (1H, m),3.80-3.67 (1H, m), 3.37-3.29 (4H, m), 3.14-2.98 (6H, 4 × s)*, 1.99-1.83(5H, s), 1.81-1.66 (2H, m), 1.16 (1H, d, J = 6.7 Hz)*, 0.94-0.84 (2H,m)*. Rt = 3.64 min, m/z = 635.3 [M]+ 58

See Ex 14 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 8.76 (0.5H, d, J = 7.2Hz)*, 8.69 (0.5H, d, J = 7.6 Hz)*, 8.03 (1H, m), 7.99-7.78 (6H, m), 7.68(1H, d, J = 8.4 Hz), 7.64- 7.55 (3H, m), 7.47-7.29 (6H, m), 7.19 (1H, d,J = 7.7 Hz), 6.69- 6.60 (1H, m), 4.74-4.58 (1H, m), 4.57-4.40 (2H, m),3.02 (4.5H, s)*, 2.97 (4.5H, s)*, 1.95-1.89 (3H, m), 1.35 (1.5H, d, J =7.0 Hz)*, 1.17 (1.5H, d, J = 6.9 Hz)*. Rt = 3.95 min, m/z = 628.4 [M]+59

(R)-1-(4- Dimethyl- aminomethyl- phenyl)- ethylamine Ex 29 ¹H NMR (400MHz, d6-DMSO): δ 8.75 (0.5H, d, J = 7.2 Hz)*, 8.69 (0.5H, d, J = 7.7Hz)*, 8.03 (1H, m), 7.99-7.78 (6H, m), 7.68 (1H, d, J = 8.4 Hz), 7.62-7.58 (3H, m), 7.48-7.41 (2H, m), 7.41-7.35 (1H, m), 7.34-7.26 (3H, m),7.22-7.15 (1H, m), 6.68- 6.60 (1H, m), 4.73-4.58 (1H, m), 4.56-4.41 (2H,m), 3.05-2.95 (9H, m)*, 1.96-1.89 (3H, m), 1.35 (1.5H, d, J = 6.7 Hz)*,1.17 (1.5H, d, J = 6.6 Hz)*. Rt = 3.95 min, m/z = 628.4 [M]+ 60

Intermed. B Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 9.08 (1H, d, J = 7.1 Hz),8.05 (1H, m), 7.96-7.83 (6H, m), 7.69-7.62 (2H, m), 7.61-7.57 (2H, m),7.35-7.26 (3H, m), 6.66- 6.62 (1H, m), 5.04-4.95 (1H, m), 4.81-4.75 (2H,m)*, 3.19- 3.10 (9H, m)*, 1.93 (1.5H, s)*, 1.92 (1.5H, s)*, 1.39-1.33(3H, m). Rt = 3.84 min, m/z = 620.4 [M]+ 61

See Ex 17 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 8.38-8.33 (1H, m), 8.01(1H, s), 7.94-7.80 (6H, m), 7.70- 7.65 (2H, m), 7.61-7.57 (2H, m),7.33-7.27 (3H, m), 6.65 (1H, d, J = 1.8 Hz), 4.41 (2H, s), 4.05-3.91(1H, m), 3.59-3.46 (2H, m), 3.21 (9H, s), 3.13-3.03 (1H, m), 2.90-2.82(1H, m), 1.91 (3H, s), 1.77-1.67 (1H, m), 1.55-1.20 (3H, m). Rt = 3.77min, m/z = 635.4 [M]+ 62

See Ex 18 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 8.89 (1H, br s), 7.92 (1H,s), 7.90-7.78 (6H, m), 7.67-7.59 (4H, m), 7.30-7.21 (3H, m), 6.61 (1H, dJ = 1.7 Hz), 4.47 (1H, br S), 3.44-3.14 (6H, m), 3.10-3.00 (6H 2 × ssignals partially obscured by water), 2.95- 2.75 (3H, br m), 2.00-1.80(4H, br m), 1.75-1.45 (4H, br m), 1.25-0.85 (3H, br m). Rt = 3.74 min,m/z = 663.4 [M]+ 63

Intermed. C Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 9.10 (0.45H, d J = 7.0Hz), 9.00 (0.55H, d J = 7.4 Hz), 8.02 (1H, s), 8.00-7.75 (6H, m),7.72-7.64 (2H, m), 7.61-7.57 (2H, m), 7.34-7.26 (3H, m), 6.67- 6.62 (1H,m), 5.04-4.90 (3H, m), 3.19-3.15 (9H, m), 1.93-1.88 (3H, m), 1.39-1.28(3H, m). Rt = 3.54 min, m/z = 620.4 [M]+ 64

See Ex 16 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 9.07-8.97 (1H, m), 8.02(1H, s), 7.96-7.80 (6H, m), 7.70- 7.56 (4H, m), 7.39 (1H, s), 7.34-7.28(3H, m), 6.65 (1H, s), 4.84-4.72 (1H, m), 4.68 and 4.65 (2H, 2 × s)*,3.01 (9H,br s), 1.92 and 1.89 (3H, 2 × s)*, 1.35 and 1.20 (3H, 2 × d J =6.8 Hz)*. Rt = 3.74 min, m/z = 619.4 [M]+ 65

See Ex 15 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 8.40-8.31 (1H, m), 8.02(1H, s), 7.95-7.88 (3H, m), 7.88- 7.78 (3H, m), 7.71-7.63 (2H, m),7.61-7.55 (2H, m), 7.35-7.25 (3H, m), 6.65 (1H, d J = 1.7 Hz), 4.00-3.88(1H, m), 3.75- 3.60 (1H, m), 3.56-3.45 (3H, m), 3.17-3.00 (10 H,overlapping s and m), 2.90-2.75 (3H, m), 1.91 (3H, s), 1.74-1.64 (1H,m), 1.52-1.334 (2H, m), 1.28-1.14 (1.3H, m)*, 1.04-0.90 (0.7H, m)*. Rt =3.72 min, m/z = 649.5 [M]+ 66

3-Methyl-3- aza- spiro[5.5] undec- 9-yl amine Ex 29 ¹H NMR (400 MHz,d6-DMSO): δ 8.40-8.31 (1H, m), 8.02 (1H, s), 7.95-7.88 (3H, m), 7.88-7.78 (3H, m), 7.71-7.63 (2H, m), 7.61-7.55 (2H, m), 7.35- 7.25 (3H, m),6.65 (1H, d J = 1.7 Hz), 4.00-3.88 (1H, m), 3.75- 3.60 (1H, m),3.56-3.45 (3H, m), 3.17-3.00 (10 H, overlapping s and m), 2.90-2.75 (3H,m), 1.91 (3H, s), 1.74-1.64 (1H, m), 1.52-1.334 (2H, m), 1.28-1.14(1.3H, m)*, 1.04-0.90 (0.7H, m)*. Rt = 3.87 min, m/z = 632.4 [M]+ 67

Cis-3- dimethylamino- methyl- cyclobutyl- amine Ex 29 ¹H NMR (400 MHz,d6-DMSO): δ 8.41 (1H, d J = 7.7 Hz), 8.00 (1H, s), 7.93-7.80 (6H, m),7.66 (2H, d J = 8.8 Hz), 7.61-7.57 (2H, m), 7.34-7.26 (3H, m), 6.64 (1H,d J = 1.8 Hz), 3.86-3.74 (1H, m), 3.36-3.28 (signal partially obscuredby water, assumed 2H), 2.98 (9H, s), 2.44-2.20 (3H, m), 1.90 (3H, s),1.78-1.66 (1H, m), 1.63-1.51 (1H, m). Rt = 3.71 min, m/z = 578.3 [M]+ 68

Trans-3- dimethylamino- methyl- cyclobutyl- amine Ex 29 ¹H NMR (400 MHz,d6-DMSO): δ 8.54 (1H, d J = 6.5 Hz), 8.01 (1H, s), 7.94-7.80 (6H, m),7.67 (2H, d J = 8.9 Hz), 7.61-7.57 (2H, m), 7.34-7.28 (3H, m), 6.64 (1H,d J = 1.8 Hz), 3.94-3.83 (1H, m), 3.40 (2H, d J = 6.8 Hz), 2.97 (9H, s),2.81-2.70 (1H, m), 2.13-2.04 (2H, m), 2.03- 1.94 (1H, m), 1.93-1.80 (4H,overlapping m and s). Rt = 3.73 min, m/z = 578.3 [M]+ 69

See Ex 19 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 9.0-8.96 (0.8H, m)*, 8.83(0.2H, d J = 7.1 Hz)*, 8.06-8.00 (1H, m), 7.96-7.80 (6H, m), 7.71-7.63(2H, m), 7.62-7.56 (2H, m), 7.35-7.26 (3H, m), 7.64 (1H, br s),4.56-4.38 (2H, m), 4.02-3.86 (1H, m), 3.62-3.48 (1.4H, m)*, 3.06-2.92(9H, m), 2.60-2.52 (peak partially obscured by solvent, 0.6H)*,2.20-2.00 (2H, m), 1.96-1.84 (3H, m), 1.68-1.36 (2.4H, m)*, 1.24-1.10(2H, m), 0.88-0.80 (1.6H, m)*. Rt = 3.70 min, m/z = 649.4 [M]+ 70

See Ex 19 Ex 30 ¹H NMR (400 MHz, d6-DMSO): δ 9.08-8.98 (0.8H, m)*, 8.85(0.2H, d, J = 6.9 Hz)*, 8.50 (1H, s), 8.06-8.00 (1H, m), 7.98- 7.76 (6H,m), 7.72-7.62 (2H, m), 7.60-7.46 (5H, m), 6.67-6.63 (1H, m), 4.60-4.40(4H, m), 4.02- 3.90 (1.4H, m)*, 3.68-2.95 (0.6H peaks partially obscuredby water)*, 2.91-2.77 (6H, m), 2.65-2.45 (1H, m, partially obscured bysolvent), 2.40-2.15 (2H, m), 1.98-1.84 (3H, m), 1.84-1.55 (2H, m),1.18-1.10 (1.2H, m)*, 0.91-0.81 (1.8H, m)*. Rt = 4.01 min, m/z = 725.4[M]+ 71

See Ex 20 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 8.99 (0.6H, d J = 6.6 Hz)*,8.88 (0.4H, d J = 7.1 Hz)*, 8.05- 8.00 (1H, m), 7.95-7.80 (6H, m),7.71-7.64 (2H, m), 7.61- 7.56 (2H, m), 7.34-7.26 (3H, m), 6.66-6.62 (1H,m), 4.49-4.38 (1H, m), 3.86-3.50 (2H, m), 3.44- 3.36 (2H, signalpartially obscured by water), 3.10-3.02 (9H, 2 × s)*, 3.00-2.94 (3H, 2 ×s)*, 1.93 (1.8H, s)*, 1.86 (1.2H, s)*,1.18-1.10 (1.2H, m)*, 0.92- 0.84(1.8H, m)*. Rt = 3.78 min, m/z = 623.4 [M]+ 72

See Ex 9 Ex 30 (using 3- Chloro- methyl- [1,2,4]- oxadi- azole) ¹H NMR(400 MHz, d6-DMSO): δ 9.89 (1H, s), 8.21 (1H, d J = 7.4 Hz), 8.01 (1H,s), 7.93- 7.80 (6H, m), 7.67 (2H, d J = 8.9 Hz), 6.64 (1H, d J = 1.8Hz), 4.89 (2H, s), 3.34-3.20 (2H, signals partially obscured by water),3.07 (6H, s), 2.20-2.10 (2H, m), 1.92-1.80 (4H, m), 1.70-1.50 (3H, m),1.28-1.00 (2H, m) Rt = 3.84 min, m/z = 660.4 [M]+ 73

See Ex 21 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 9.15 (d, 0.6H, J = 8.50Hz)*, 9.04 (d, 0.4H, J = 8.50 Hz)*, 8.06 (s, 1H), 7.97-7.77 (m, 6H),7.67 (d, 1H, J = 8.65 Hz), 7.62- 7.55 (m, 3H), 7.45-7.40 (m, 1H),7.35-7.25 (m, 3H), 6.67-6.61 (m, 1H), 4.77-4.62 (m, 1H), 4.62- 4.52 (m,2H), 3.07 (s, 9H), 1.99- 1.87 (m, 3H), 0.81 (q, 2H, J = 3.24 Hz), 0.66(d, 1.5H, J = 6.76 Hz)*, 0.59 (d, 1.5H, J = 6.73 Hz)*. Rt = 3.90 min,m/z = 647.4 [M]+ 74

See Ex 22 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 9.06-8.98 (m, 1H), 8.04 (s,1H), 7.96-7.81 (m, 6H), 7.67 (d, 1H, J = 8.95 Hz), 7.64-7.56 (m, 3H),7.41 (s, 1H), 7.34-7.26 (m, 3H), 6.64 (d, 1H, J = 1.71 Hz), 4.75-4.59(m, 3H), 3.07-2.94 (m, 9H), 1.99-1.86 (m, 3H), 1.86- 1.52 (m, 2H), 0.75(t, 1H, J = 7.27 Hz), 0.57 (t, 2H, J = 7.27 Hz). Rt = 3.80 min, m/z =633.4 [M]+ 75

See Ex 9 Ex 30 (using 3- Chloro- methyl-5- methyl- isox- azole) ¹H NMR(400 MHz, d6-DMSO): δ 8.21 (1H, d J = 7.4 Hz), 8.01 (1H, s), 7.93-7.88(3H, m), 7.88- 7.80 (3H, m), 7.67 (2H, d J = 8.8 Hz), 6.64 (1H, d J =1.8 Hz), 6.51 (1H, d J = 0.8 Hz), 4.63 (2H, s), 3.36-3.15 (1H signalpart obscured by water), 2.99 (6H, s), 2.48 (3H, s signal part obscuredby solvent), 2.22-2.10 (2H, m), 1.96-1.80 (4H, m), 1.75-1.50 (3H, m),1.32-1.02 (3H, m). Rt = 3.96 min, m/z = 673.4 [M]+ 76

See Ex 9 Ex 30 (using 5- Chloro- methyl-1,3- dimethyl- 1H-pyra- zole) ¹HNMR (400 MHz, d6-DMSO): δ 8.32 (1H, d J = 7.5 Hz), 8.02 (1H, s),7.94-7.89 (3H, m), 7.88- 7.80 (3H, m), 7.68 (2H, d J = 8.8 Hz), 6.65(1H, d J = 1.7 Hz), 6.31 (1H, s), 4.58 (2H, s), 3.82 (3H, s), 3.50-3.20(1H signal part obscured by water), 2.86 (6H, s), 2.24-2.12 (5H, m),2.02-1.82 (4H, m), 1.74-1.52 (4H, m), 1.36-1.20 (1H, m), 1.18-1.06 (1H,m). Rt = 3.87 min, m/z = 686.5 [M]+ 77

Intermed. J Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 8.19 (1H, d J = 7.4 Hz),8.06 (1H, t J = 5.5 Hz), 8.01 (1H, s), 7.90-7.79 (6H, m), 7.66 (2H, d J= 8.8 Hz), 7.61-7.57 (2H, m), 7.34-7.27 (3H, m), 6.64 (1H, d J = 1.7Hz), 3.47-3.40 (2H, m), 3.35-3.25 (2H, signal obscured by water),3.20-3.10 (1H, m), 3.06 (9H, s), 2.08-1.98 (1H, m), 1.90 (3H, s),1.78-1.64 (3H, m), 1.50-1.40 (1H, m), 1.39-1.10 (3H, m), 1.01-0.90 (1H,m). Rt = 3.76 min, m/z = 663.4 [M]+ 78

See Ex 24 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 9.10 (s, 1H), 8.03 (s, 1H),7.96-7.80 (m, 6H), 7.63-7.55 (m, 4H), 7.36-7.25 (m, 4H), 6.59 (d, 2H, J= 1.75 Hz), 4.63 (s, 2H), 2.95 (s, 9H), 1.91 (s, 3H), 1.40 (d, 6H). Rt =3.76 min, m/z = 633.4 [M]+ 79

See Ex 23 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 9.11 (s, 1H), 8.03 (s, 1H),7.95-7.83 (m, 6H), 7.65 (d, 2H, J = 8.85 Hz), 7.61-7.56 (m, 2H),7.34-7.27 (m, 4H), 6.64 (d, 1H, J = 1.76), 4.59 (s, 2H), 2.97 (s, 9H),1.91 (s, 3H), 1.38 (s, 2H), 1.32-1.18 (m, 1H), 0.82-0.67 (m, 1H). Rt =3.69 min, m/z = 631.3 [M]+ 80

Intermed. K Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 8.52 (1H, d J = 7.1 Hz),8.10-8.04 (2H, m), 7.94-7.80 (6H, m), 7.65 (2H, d J = 8.8 Hz), 7.61-7.57(2H, m), 7.34-7.26 (3H, m), 6.64 (1H, d J = 1.8 Hz), 3.57-3.50 (1H, m),3.48-3.40 (2H, m), 3.36-3.28 (1H, signal obscured by water), 3.07 (9H,s), 2.16-2.08 (2H, m), 1.94 (3H, s), 1.56-1.10 (8H, m). Aliphaticsignals are broad overlapped and partially obscured by the water signal.Rt = 3.67 min, m/z = 663.4 [M]+ 81

Intermed. P Ex 29 ¹H NMR (400 MHz, DMSO d6): δ 8.43 (1H, d J = 7.7 Hz),8.08 (1H, t J = 5.7 Hz), 8.01 (1H, s), 7.92-7.80 (6H, m), 7.65 (2H, d J= 8.9 Hz), 7.61-7.57 (3H, m), 7.34-7.28 (5H, m) (bezylate ~1.6 eq), 6.64(1H, d J = 1.8 Hz), 3.89-3.77 (1H, m), 3.49-3.41 (2H, m), 3.36-3.28(peak obscured by water signal), 3.06 (9H, s), 2.65-2.55 (1H, m),2.32-2.10 (2H, m), 1.98-1.85 (4H, m), 1.84- 1.74 (1H, m). Rt = 3.60 min,m/z = 635.4 [M]+ 82

Intermed. Q Ex 29 ¹H NMR (400 MHz, DMSO d6): δ 8.23 (1H, d J = 7.4 Hz),8.02 (1H, s), 7.94-7.78 (6H, m), 7.67 (2H, d J = 8.4 Hz), 7.62-7.56 (2H,m), 7.34-7.26 (3H, m), 6.64 (1H, d J = 1.8 Hz), 4.42 (2H, br s),3.65-3.60 (2H, m), 3.25-3.15 (1H, m), 3.10 (9H, s), 2.32- 2.23 (1H, m),1.92-1.80 (5H, m), 1.78-1.70 (1H, m), 1.50-1.14 (4H, m), 1.06-0.93 (1H,m). Rt = 3.94 min, m/z = 664.4 [M]+ 83

Intermed. O Ex 29 ¹H NMR (400 MHz, DMSO d6): δ 8.45 (1H, d J = 7.6 Hz),8.08 (1H, t J = 5.7 Hz), 8.00 (1H, s), 7.93-7.80 (6H, m), 7.65 (2H, d J= 8.8 Hz), 7.61-7.57 (2H, m), 7.34-7.26 (3H, m), 6.64 (1H, d J = 1.8Hz), 4.12-4.00 (1H, m), 3.49-3.42 (2H, m), 3.35-3.30 (2H, signalobscured by water), 3.07 (9H, s), 2.83-2.74 (1H, m), 2.26-2.04 (3H, m),1.96- 1.86 (4H, m). Rt = 3.66 min, m/z = 635.4 [M]+ 84

See Ex 25 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 8.43 (s, 1H), 8.03 (s, 1H),7.96-7.80 (m, 6H), 7.65 (d, 2H, J = 7.84 Hz), 7.61-7.56 (m, 2H),7.34-7.25 (m, 3H), 6.64 (d, 1H, J = 1.72 Hz), 4.44-4.25 (m, 2H), 3.91(br s, 1H), 3.37 (br s, 1H), 3.20 (s, 9H), 3.06-2.92 (m, 1H), 2.88-2.68(m, 1H), 1.95 (s, 3H), 1.86 (d, 1H, J = 13.33 Hz), 1.66 (t, 1H, J =14.32 Hz), 1.49- 1.19 (m, 2H), 1.00 (s, 3H). Rt = 3.86 min, m/z = 649.4[M]+ 85

Intermed. I Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 9.11 and 9.05 (1H, 2 × d,J = 7.1 Hz)*, 8.08-8.01 (1H, m), 7.97-7.80 (6H, m), 7.72-7.61 (3H, m),7.61-7.56 (2H, m), 7.35-7.26 (3H, m), 6.65 (1H, s), 4.99-4.88 (1H, m),4.58 and 4.56 (2H, 2 × s)*, 3.02 and 3.04 (9H, 2 × s)*, 1.94 and 1.92(3H, 2 × s)*, 1.45 and 1.29, 2 × d, J = 7 Hz)*. Rt = 3.79 min, m/z =635.3 [M]+ 86

See Ex 27 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 8.50-8.36 (0.5H, m)*, 8.18(0.5H, d, J = 7.52 Hz)*, 8.03- 7.96 (1H, m), 7.94-7.72 (7H, m),7.72-7.63 (2H, m), 7.63-7.54 (2H, m), 7.36-7.25 (3H, m), 6.72 (0.4H, d,J = 1.80 Hz)*, 6.63 (0.6 Hz, d, J = 1.75 Hz)*, 4.08-4.03 (2H, m),3.63-3.56 (1H, m), 3.21- 3.17 (9H, m), 3.03-2.90 (2H, m), 2.04-1.95(0.6H, m)*, 1.90 (1.4H, s)*, 1.81-1.55 (4H, m), 1.47-1.20 (2H, m),1.03-0.79 (2H, m). Rt = 3.85 min, m/z = 663.5 [M]+ 87

See Ex 26 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 8.38 (1H, d, J = 7.60 Hz),8.23 (1H, d, J = 7.42 Hz), 8.01 (1H, s), 7.94-7.78 (6H, m), 7.66 (2H, d,J = 8.82 Hz), 7.62-7.56 (2H, m), 7.34-7.26 (3H, m), 6.64 (1H, d, J =1.75 Hz), 4.00 (2H, s), 3.58-3.46 (1H, m), 3.18 (10H, s), 1.89 (3H, s),1.79-1.66 (3H, m), 1.46-1.37 (1H, m), 1.33- 0.96 (4H, m). Rt = 3.84 min,m/z = 649.3 [M]+ 88

Intermed. R Ex 29 ¹H NMR (400 MHz, CDCl₃) δ 8.32 (1H, d, J = 7.0 Hz),7.88- 7.78 (3H, m), 7.78-7.66 (4H, m), 7.64-7.56 (3H, m), 7.56-7.49 (1H,m), 7.39-7.31 (3H, m), 6.65 (1H, d, J = 1.5 Hz), 4.81-4.67 (1H, m),4.31-4.09 (1H, m), 3.99- 3.88 (1H, m), 3.50-3.37 (1H, m), 3.35-3.09(10H, m), 2.66- 2.51 (1H, m), 2.46-2.27 (2H, m), 2.23-2.10 (1H, m),2.03-1.94 (1H, m), 1.93-1.85 (3H, m), 1.85- 1.36 (7H, m), 1.22-0.95 (2H,m). Rt = 3.80 min, m/z = 703 [M]⁺ 89

Intermed. L Ex 29 ¹H NMR (400 MHz, CDCl₃) δ 8.35 (1H, d, J = 7.6 Hz),7.89- 7.84 (2H, m), 7.81 (1H, d, J = 1.8 Hz), 7.78-7.66 (4H, m),7.64-7.56 (3H, m), 7.54-7.51 (1H, m), 7.39-7.32 (3H, m), 6.56 (1H, d, J= 1.6 Hz), 3.89-3.71 (4H, m), 3.52-3.39 (1H, m), 3.34 (9H, s), 3.13 (3H,s), 2.38 (1H, tt, J = 11.7, 6.4 Hz), 2.04-1.96 (1H, m), 1.91-1.79 (4H,m), 1.75-1.66 (2H, m), 1.52-1.39 (2H, m), 1.26-1.01 (2H, m). Rt = 3.85min, m/z = 677 [M]⁺ 90

Intermed. S Ex 29 ¹H NMR (400 MHz, CDCl₃) δ 8.15 (1H, d, J = 7.7 Hz),8.10 (1H, d, J = 8.1 Hz), 7.88-7.82 (2H, m), 7.80 (1H, d, J = 1.9 Hz),7.77-7.66 (3H, m), 7.65- 7.62 (1H, m), 7.62-7.52 (3H, m), 7.40-7.35 (3H,m), 6.54 (1H, d, J = 1.9 Hz), 4.21-4.11 (1H, m), 4.05-3.93 (2H, m), 3.51(3H, m), 3.37-3.24 (3H, m), 3.19-3.11 (3H, s), 2.23-2.09 (2H, m), 2.04-1.90 (3H, m), 1.89-1.83 (3H, m), 1.81-1.72 (1H, m), 1.70- 1.53 (4H, m),1.42-1.28 (2H, m), 0.87-0.63 (2H, m). Rt = 3.79 min, m/z = 689 [M]⁺ 91

See Ex 28 Ex 29 ¹H NMR (400 MHz, d6-DMSO): δ 9.01 (1H, td, J = 6.47,56.69 Hz), 8.03 (1H, d, J = 7.69 Hz), 7.97-7.78 (6H, m), 7.72- 7.63 (2H,m), 7.61-7.56 (2H, m), 7.35-7.26 (3H, m), 6.67-6.62 (2H, m), 4.58-4.26(2H, m), 3.56- 3.36 (4H, m), 3.19-3.01 (6H, m), 2.84 (2H, d, J = 9.09Hz), 2.76 (1H, d, J = 14.75 Hz), 2.27- 1.99 (2H, m), 1.94 (2H, d, J =7.62 Hz), 1.88 (1H, d, J = 5.27 Hz), 1.67-1.44 (2H, m), 1.12 (1.5H, d, J= 6.63 Hz)*, 0.83 (1.5H, t, J = 6.84 Hz)*. Rt = 3.65 min, m/z = 649.3[M]+

Example 92.{2-[(4-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidine-1-carbonyl)-amino]-ethyl}-trimethyl-ammoniumbenzene sulfonate

Intermediate 92A.4-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester

Intermediate 92A was synthesized from 4-amino-1-BOC-piperidine by themethod of Example 1 in a yield of 85%.

LCMS (Method U2) Rt=2.03 min., m/z=658.4 [M+Na]+

Intermediate 92B.5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid piperidin-4-ylamide

Intermediate 92A (525 mg, 0.83 mmol) was stirred in DCM (6 mL) with TFA(1.5 mL) and water (50 mg) for 1.5 h. The mixture was diluted with moreDCM and washed with aqueous NaHCO₃ solution. The aqueous phase wasextracted with more DCM and the combined organics dried over Na₂SO₄ andevaporated to give Intermediate 92B as a pale yellow foam (466 mg).

LCMS (Method U2) Rt=1.30 min., m/z=536.3 [M+H]+

Intermediate 92C.4-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidine-1-carboxylicacid (2-dimethylamino-ethyl)-amide

1,1′-Carbonyldiimidazole (73.5 mg, 0.45 mmol) was stirred in dry THF(1.5 mL) as N,N-dimethylethylenediamine (35 mg, 0.40 mmol) was added.After stirring for 10 min., a solution of Intermediate 92B (175 mg, 0.33mmol) in dry THF (1.5 mL) was added. The mixture was stirred for 5 h andthe solvent evaporated and the concentrate was partitioned between EtOAcand water. The organic phase was washed with water and with brine, dried(Na₂SO₄) and evaporated. Purified by SPE on silica (5 g) eluting with 5%MeOH in DCM with additional 2M methanolic ammonia (1%, 2%, 3% and 4%)added stepwise to afford Intermediate 92C (121 mg, 57%).

LCMS (Method 7) Rt=2.41 min., m/z=650.1 [M+H]+

{2-[(4-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidine-1-carbonyl)-amino]-ethyl}-trimethyl-ammoniumbenzene sulfonate

The title compound was prepared from Intermediate 92C using the methodin Example 29.

¹H NMR (400 MHz, d6-DMSO): δ 8.30 (1H, d, J=7.0 Hz), 8.01 (1H, br s),7.93-7.88 (3H, m), 7.88-7.79 (3H, m), 7.69-7.64 (2H, m), 7.61-7.56 (2H,m), 7.35-7.26 (3H, m), 6.82 (1H, t, J=5.8 Hz), 6.64 (1H, d, J=1.8 Hz),3.63 (2H, br t, J=15 Hz), 3.48-3.36 (3H, m), 3.35-3.29 (2H, m, partiallyobscured by water), 3.07 (9H, s), 2.82 (2H, br t, J=11.4 Hz), 1.91 (3H,s), 1.67-1.56 (1H, m), 1.42-1.32 (1H, m), 1.28-1.15 (1H, m), 1.07-0.93(1H, m).

LCMS (Method 3) Rt=3.74 min, m/z=665.3 [M]+

Example 93.[2-(4-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidine-1-carbonyloxy)-ethyl]-trimethyl-ammoniumbenzene sulfonate

Intermediate 93A.4-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidine-1-carboxylicacid 2-dimethylamino-ethyl ester

Intermediate 93A was synthesized by a similar procedure to Intermediate92C, using N,N-dimethylethanolamine. The mixture of1,1′-carbonyldiimidazole (21 mg, 0.13 mmol) and N,N-dimethylethanolamine(10 mg, 0.11 mmol) was stirred for 1 h prior to addition of Intermediate92B (50 mg, 0.093 mmol). Purification by silica SPE (5 g) eluting with5% and 10% MeOH in DCM afforded Intermediate 93A (25 mg, 42%). LCMS(Method U2) Rt=1.38 min., m/z=651.4 [M+H]+

[2-(4-{[5-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidine-1-carbonyloxy)-ethyl]-trimethyl-ammoniumbenzene sulfonate

The title compound was prepared from Intermediate 93A using the methodin Example 29.

¹H NMR (400 MHz, d6-DMSO): δ 8.33 (1H, d, J=7.1 Hz), 8.02 (1H, s),7.95-7.88 (3H, m), 7.88-7.80 (3H, m), 7.66 (2H, m), 7.62-7.59 (2H, m),7.35-7.26 (3H, m), 6.64 (1H, d, J=1.6 Hz), 4.41 (2H, s), 3.74-3.56 (4H,m), 3.53-3.41 (1H, m), 3.10 (9H, s), 2.96 (2H, br s), 1.92 (3H, s),1.74-1.58 (1H, m), 1.46-1.19 (2H, m), 1.13-0.97 (1H, m). LCMS (Method 3)Rt=3.71 min, m/z=664.3 [M]+

Example 94.[2-(4-{[1-(4-Cyano-phenyl)-5′-methyl-2′-oxo-1′-(3-trifluoromethyl-phenyl)-1′,2′-dihydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-amino}-piperidin-1-yl)-2-oxo-ethyl]-trimethyl-ammoniumbenzene sulfonate

Intermediate 94A. 4-(2-Bromo-imidazol-1-yl)-benzonitrile

4-Imidazol-1-yl-benzonitrile (5.0 g, 29.6 mmol) was dissolved in dioxaneand N-bromosuccinimide (5.26 g, 29.6 mmol) was added. The solution washeated at 60° C. for 2 h. The solution was decanted from a gummy residueand evaporated to give a yellow solid. This was triturated with EtOAc togive a cream solid which was further purified by chromatography usingEtOAc as eluant to afford Intermediate 11 (0.79 g) as a pale yellowsolid.

LCMS (Method 1) Rt=2.44 min., m/z 248 and 250 (Br isotopes)

Intermediate 94B.4-[2′-Ethoxy-5′-methyl-1′-(3-trifluoromethyl-phenyl)-1′H-[2,4′]biimidazolyl-1-yl]-benzonitrile

2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (19 mg, 0.04mmol),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)palladium(II)dichloride (15.7 mg, 0.02 mmol), tetrahydroxydiboron (270 mg, 3 mmol)and potassium acetate (294 mg, 3 mmol) were mixed in a nitrogen filledvial. A solution of4-bromo-2-ethoxy-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-imidazole(Intermediate A4, 349 mg, 1 mmol) in IMS (10 ml) was added and thesolution heated at 80° C. for 2 h. A solution of K₂CO₃ (1.8M, 1.66 ml)was added followed by a suspension of4-(2-bromo-imidazol-1-yl)-benzonitrile (Intermediate 94A, 248 mg, 1mmol) in THF. Heating was continued overnight at 80° C. After cooling,the mixture was filtered through celite, washing with EtOAc, andevaporated to dryness. The residue was extracted into EtOAc, decanted,dried over Na₂SO₄ filtered and evaporated. Purification was performed bysilica gel chromatography eluting with 20% to 100% EtOAc-cyclohexane.The third eluted component was the title compound (91 mg, 21%).

LCMS (Method 2) Rt=2.73 min., m/z 438.3

Intermediate 94C.4-[5′-Methyl-2′-oxo-1′-(3-trifluoromethyl-phenyl)-2′,3′-dihydro-1′H-[2,4′]biimidazolyl-1-yl]-benzonitrile

4-[2′-Ethoxy-5′-methyl-1′-(3-trifluoromethyl-phenyl)-1′H-[2,4′]biimidazolyl-1-yl]-benzonitrile(Intermediate 94B, 170 mg, 0.39 mmol), acetone (5 ml) and 1M HCl (3 ml)were heated together at 60° C. for 3.5 h. Concentrated HCl (0.5 ml) wasadded and heating continued overnight. The mixture was cooled and mostof the acetone removed by evaporation. The solution was basified withaqueous NaHCO₃ and the white solid title compound filtered off and driedat 50° C. Yield 150 mg (94%).

LCMS (Method 3): Rt=3.61 min, m/z 410.1 [M+H]+

¹H NMR (400 MHz, d6-DMSO): δ 10.47 (1H, s), 8.05-7.99 (2H, m), 7.79-7.73(3H, m), 7.72 (1H, d, J=1.4 Hz), 7.68-7.63 (1H, m), 7.63-7.58 (2H, m),7.28 (1H, d, J=1.4 Hz), 1.70 (3H, s).

Intermediate 94D.1-(4-Cyano-phenyl)-5′-methyl-2′-oxo-1′-(3-trifluoromethyl-phenyl)-1′,2′-dihydro-1H-[2,4′]biimidazolyl-3′-carboxylicacid [1-(2-dimethylamino-acetyl)-piperidin-4-yl]-amide

To intermediate 94C (50 mg, 0.122 mmol) in DCM (2 mL) was addedtriethylamine (25 mg, 0.244 mmol) and 4-nitrophenyl chloroformate (30mg, 0.146 mmol). The mixture was stirred for 1 h at room temperature.1-(4-Amino-piperidin-1-yl)-2-dimethyl-amino-ethanone (45 mg, 0.244 mmol)in DCM (0.5 ml) was added and the mixture was stirred for 3 h. Themixture was partitioned between DCM and 10% K₂CO₃ solution, the aqueousextracted a further ×2 with DCM and the combined extracts dried (MgSO₄)and evaporated.

LCMS (Method U2) Rt=0.99 min, m/z=621 [M+H]+. The product was usedwithout purification for the next step.

[2-(4-{[1-(4-Cyano-phenyl)-5′-methyl-T-oxo-1′-(3-trifluoromethyl-phenyl)-1′,2′-dihydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-amino}-piperidin-1-yl)-2-oxo-ethyl]-trimethyl-ammoniumbenzene sulfonate

The crude Intermediate 94D (0.12 mmol) was stirred with methylbenzenesulphonate (23 mg, 0.13 mmol) in THF (0.5 mL) at 20° C.overnight. The product was purified by HPLC (C18, 0% to 50%acetonitrile/water containing 0.1% formic acid. The appropriatefractions were freeze dried to give the title compound (34 mg, 35%). ¹HNMR (400 MHz, d6-DMSO): δ 8.49 (1H, s), 8.25 (1H, d, J=7.25 Hz), 7.98(1H, s), 7.96 (2H, d, J=8.75 Hz), 7.91-7.86 (1H, m), 7.86-7.77 (2H, m),7.72 (1H, d, J=1.42 Hz), 7.61-7.57 (1H, m), 7.55 (2H, d, J=8.72 Hz),7.21 (1H, d, J=1.41 Hz), 4.43 (2H, s), 4.07-3.94 (1H, m), 3.65-3.45 (2H,m), 3.21 (9H, s), 3.15-3.00 (2H, m), 2.94-2.82 (1H, m), 1.90 (3H, s),1.65 (2H, br s), 1.44-1.03 (3H, m).

LCMS (Method 3) Rt=3.16 min, m/z=635.3 [M]+.

Biological Assay

Compounds of this invention were tested for potency in a humanneutrophil elastase (HNE) enzyme activity assay.

HNE Enzyme Assay

Assays were performed in 96-well plates in a total assay volume of 100μL. The final concentration of elastase enzyme (human leukocyteelastase, Sigma E8140) was 0.00072 U/mL. The peptide substrate(MeOSuc-Ala-Ala-Pro-Val-AMC, Calbiochem #324740) was used at a finalconcentration of 100 μM. The final concentration of DMSO was 1% in theassay buffer (0.05M Tris.HCl, 0.1M NaCl, 0.1M CaCl₂, 0.0005% Brij-35, pH7.5). The enzymatic reaction was started by addition of the enzyme andincubated at 25° C. for 30 minutes. After incubation, the reaction wasstopped by addition of soybean trypsin inhibitor (Sigma T9003) at afinal concentration of 50 μg/well. Fluorescence was measured using aMolecular Devices fluorescence plate reader using 380 nm excitation and460 nm emission wavelengths.

A concentration response to each compound was performed and the effectof compound in each experiment was expressed as a percentage inhibitionof the control enzyme fluorescence. Dose response curves were plottedand compound potency (IC₅₀) was determined. Compounds were tested in atleast two separate experiments. IC₅₀ values for tested Examples,representative of the invention, are shown in Table:

TABLE HNE inhibi- Example tion 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, ++++ 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 47, 49, 50, 51, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,75, 76, 77, 78, 79, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 942, 33, 45, 46, 48, 52, 53, 54, 55, 59, 80 +++

In the table above, FINE enzyme inhibition (IC₅₀ values) are indicatedas follows:

1-10 nM ‘+++’;

<1 nM ‘++++’.

LPS/fMLP Model

Male Sprague-Dawley rats were lightly anaesthetised and given vehicle(for example 0.2% Tween 80 in saline for wet formulation studies orlactose for dry powder studies) or compound, i.t., at the desiredpre-dose time (prior to fMLP administration e.g. 1 h, 12 h or 24 h)

Four hours prior to fMLP administration, animals were lightlyanaesthetized and given LPS (for example 0.5 ml/kg of 20 μg/ml PBSsolution) by the i.t. route. Thirty to forty minutes prior tofMLP-administration, animals were terminally anaesthetised withurethane. Animals were placed on a heat mat and anaesthesia wasmaintained until animals were killed and subjected to BAL.

Four hours after LPS-challenge, rats were given fMLP (for example 0.5ml/kg of 0.6 mg/ml PBS solution) by the i.t. route.

Animals were killed one hour after fMLP-administration, the tracheacannulated and BALF collected. An elastase activity assay was performedto determine the level of elastase present in the BALF.

HNE Model

Male Sprague-Dawley rats were lightly anaesthetized and given vehicle(for example 0.2% Tween 80 in saline for wet formulation studies orlactose for dry powder studies) or compound, i.t.

Thirty to forty minutes prior to HNE-administration, animals wereterminally anaesthetised with urethane. Animals were placed on a heatmat and anaesthesia was maintained until animals were killed for BAL.

Three hours after compound/vehicle administration, animals were givenPBS as control or HNE (for example 0.1 ml of a 1000 U/ml solution inPBS) by the i.t. route.

Animals were killed one hour after iHNE-administration, the tracheacannulated and BALF collected. Red blood cells accumulation in BALF wasassessed spectrophotometrically, as a measure of BALF hemoglobincontent.

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

As used herein the words “a” and “an” and the like carry the meaning of“one or more.”

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

1. A compound of formula (I):

wherein A is:

X is:

R₁ is one of the following groups:

n is an integer from 1 to 4; m is 0 or an integer from 1 to 4; t is 0 oran integer from 1 to 4; y is an integer from 1 to 4; w is an integerfrom 1 to 4; z is 0 or 1; l is 0 or 1; R₂ is —H or linear or branched—(C₁-C₄)alkyl; R₃ is linear or branched —(C₁-C₄)alkyl or R₂ and R₃ mayform together a cycloalkyl; R₄ is -arylene-(C₁-C₄)alkylene-NR_(d)R_(e),-arylene-(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),-heteroarylene-(C₁-C₄)alkylene-NR_(d)R_(e),-heteroarylene-(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c) and heteroaryl, whereinany of such arylene-(C₁-C₄)alkylene-NR_(d)R_(e),-arylene-(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),-heteroarylene-(C₁-C₄)alkylene-NR_(d)R_(e),-heteroarylene-(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c) and heteroaryl may beoptionally substituted by one or more —(C₁-C₄)alkyl or R₄ is one of thefollowing groups:

R₅ is aryl-(C₁-C₄)alkylenoxy-, linear or branched(C₁-C₄)alkyl-OC(O)—NH—, —(CH₂)_(t)—NR_(d)R_(e),—(CH₂)_(t)—N⁺R_(a)R_(b)R_(c), —C(O)—N(R₁₀)(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)N(R₁₀)(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),—C(O)O(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)O(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),—(CH₂)_(t)NHC(O)—(C₁-C₄)alkylene-NR_(d)R_(e),—(CH₂)_(t)NHC(O)—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c), or one of thefollowing groups

R₆ is —H, —(C₁-C₄)alkyl, aryl-(C₁-C₄)alkylene-OCO—, CF₃C(O)—,aryl-(C₁-C₄)alkylene, linear or branched (C₁-C₄)alkyl-OC(O)—,—C(O)—(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),—C(O)O—(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)O—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),—C(O)—N(R₁₀)(C₁-C₄)alkylene-NR_(d)R_(e), or—C(O)N(R₁₀)(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c); R_(a) is —(C₁-C₄)alkyl;R_(b) is —(C₁-C₄)alkyl; R_(c) is —(C₁-C₄)alkyl, aryl-(C₁-C₄)alkylene orheteroaryl-(C₁-C₄)alkylene, wherein said heteroaryl-(C₁-C₄)alkylene maybe optionally substituted by one or more —(C₁-C₄)alkyl groups; R_(d) is—H or —(C₁-C₄)alkyl; R_(e) is —H or —(C₁-C₄)alkyl; R₇ is —H or—(C₁-C₄)alkyl; R₈ is —H or —(C₁-C₄)alkyl; R₉ is heterocycloalkyl,heterocycloalkyl-(C₁-C₄)alkylene-, (C₁-C₄)alkylene-NR_(d)R_(e) and(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c); R₁₀ is —H or —(C₁-C₄)alkyl; and * and#, indicate the points of attachment for the radical groups to the restof the molecule, wherein any of such heterocycloalkyl, aryl, heteroaryland aryl-(C₁-C₄)alkylene may be optionally substituted by one or moregroups independently selected from (C₁-C₄)alkyl and OR₇ and wherein thenitrogen atom in the heterocycloalkyl and heteroaryl groups may bequaternized, or a pharmaceutically acceptable salt thereof.
 2. Acompound or salt according to claim 1, wherein A is

X is

n is 2 or 3; m is 0 or 2; R₇ is —H; R₅ is aryl-(C₁-C₄)alkylenoxy-,linear or branched (C₁-C₄)alkyl-OC(O)—NH,C(O)O(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),—(CH₂)NHC(O)—(C₁-C₄)alkylene-NR_(d)R_(e),—(CH₂)NHC(O)—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c), or—C(O)N(R₁₀)(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c), — wherein t is 0 or 1,R_(a) and R_(b) are independently —(C₁-C₄)alkyl, R_(c) is —(C₁-C₄)alkyl,heteroaryl-(C₁-C₄)alkylene or aryl-(C₁-C₄)alkylene, R_(d) and R_(e) areindependently —(C₁-C₄)alkyl, R₁₀ is —H or —(C₁-C₄)alkyl.
 3. A compoundor salt according to claim 1, wherein, A is

X is

n is 1 or 2; m is 1 or 2; R₇ is —H; R₅ is —(CH₂)_(t)—NR_(d)R_(e), or—(CH₂)_(t)—N⁺R_(a)R_(b)R_(c), wherein t is 0 or 1, R_(a) and R_(b) areindependently —(C₁-C₄)alkyl, R_(e) is —(C₁-C₄)alkyl,heteroaryl-(C₁-C₄)alkylene or aryl-(C₁-C₄)alkylene.
 4. A compound orsalt according to claim 1, wherein A is

X is

n is 2; m is 2; R₇ is —H; R₅ is

R_(a) is —(C₁-C₄)alkyl; R_(b) is —(C₁-C₄)alkyl; R₁₀ is —H or—(C₁-C₄)alkyl.
 5. A compound or salt according to claim 1, wherein A is

X is

n is 2; m is 2; R₇ is —H; R₅ is

R_(a) is —(C₁-C₄)alkyl; R_(b) is —(C₁-C₄)alkyl; R_(c) is —(C₁-C₄)alkyl.6. A compound or salt according to claim 1, wherein A is

X is

n is 2; m is 2; R₇ is —H or —(C₁-C₄)alkyl; R₆ isaryl-(C₁-C₄)alkylenoxy-, aryl-(C₁-C₄)alkylene-OCO—, CF₃C(O)—,—C(O)—(C₁-C₄)alkylene-NR_(d)R_(e),—C(O)O—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c),—C(O)N(R₁₀)(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c), or—C(O)—(C₁-C₄)alkylene-N⁺R_(a)R_(b)R_(c) wherein R_(d) is —H or—(C₁-C₄)alkyl; R_(e) is —H or —(C₁-C₄)alkyl, R_(a) is —(C₁-C₄)alkyl;R_(b) is —(C₁-C₄)alkyl; R_(c) is selected from —(C₁-C₄)alkyl; R₁₀ is —Hor —(C₁-C₄)alkyl.
 7. A compound or salt according to claim 1, wherein Ais

X is

n is 1 or 2; m is 2; R₇ is —H or —(C₁-C₄)alkyl; R_(a) and R_(b) are eachindependently —(C₁-C₄)alkyl.
 8. A compound or salt according to claim 1,wherein A is

X is

n is 2; m is 2; R₇ is —H; R₅ is —(CH₂)_(t)—N⁺R_(a)R_(b)R_(c), wherein tis 1, R_(a) and R_(b) are each independently —(C₁-C₄)alkyl, and R_(c) isaryl-(C₁-C₄)alkylene.
 9. A compound, which is selected in the groupconsisting of:5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid trans-(4-dimethylaminomethyl-cyclohexyl)-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid ((1 S,2S)-2-benzyloxy-cyclopentyl)-amide;4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidine-1-carboxylicacid benzyl ester;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid [1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid ((S)-1-pyridin-4-yl-ethyl)-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid ((R)-1-pyridin-4-yl-ethyl)-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid [3-(4-methoxy-benzyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-amide;(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-carbamicacid tert-butyl ester;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid (trans-4-dimethylamino-cyclohexyl)-amide; (3aS,5R,6aR)-5-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid [(S)-1-methyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;(3aR,5S,6aS)-5-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid tert-butyl ester5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid [(S)-1-(1-methyl-piperidin-4-ylcarbamoyl)-ethyl]-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid [(S)-1-(4-dimethylaminomethyl-phenyl)-ethyl]-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid [1-(3-dimethylamino-propionyl)-piperidin-4-yl]-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid [(S)-1-(5-dimethylaminomethyl-oxazol-2-yl)-ethyl]-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid [1-(2-dimethylamino-acetyl)-piperidin-4-yl]-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid{(S)-1-[methyl-(1-methyl-piperidin-4-ylmethyl)-carbamoyl]-ethyl}-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid[(S)-2-(4-dimethylamino-piperidin-1-yl)-1-methyl-2-oxo-ethyl]-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid {(S)-1-[(2-dimethylamino-ethyl)-methyl-carbamoyl]-ethyl}-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid [(S)-1-(5-dimethylaminomethyl-oxazol-2-yl)-2-methyl-propyl]-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid [(S)-1-(5-dimethylaminomethyl-oxazol-2-yl)-propyl]-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid [1-(5-dimethylaminomethyl-oxazol-2-yl)-cyclopropyl]-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid [1-(5-dimethylaminomethyl-oxazol-2-yl)-1-methyl-ethyl]-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid [1-(2-dimethylamino-acetyl)-4-methyl-piperidin-4-yl]-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid [trans-4-(2-dimethylamino-acetylamino)-cyclohexyl]-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid {trans-4-[(2-dimethylamino-acetyl amino)-methyl]-cyclohexyl}-amide;5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carboxylicacid {(S)-1-[methyl-(1-methyl-piperidin-4-yl)-carbamoyl]-ethyl}-amide;(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-trimethyl-ammoniumbenzene sulfonate;benzyl-(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-dimethyl-ammoniumbromide;(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-ethyl-dimethyl-ammoniumbenzene sulfonate;4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-1,1-dimethyl-piperidiniumbenzenesulfonate;(R)-3-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-1,1-dimethyl-pyrrolidiniumbenzenesulfonate;(S)-3-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-1,1-dimethyl-pyrrolidiniumbenzenesulfonate;4-(1-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-1,1-dimethyl-piperidiniumbenzene sulfonate;(1S,3R,5R)-3-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octanebenzene sulfonate;(3aS,5R,6aR)-5-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-2,2-dimethyl-octahydro-cyclopenta[c]pyrroliumbenzene sulfonate;4-((S)-1-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-1-methyl-pyridiniumbenzene sulfonate;(1R,3S,5S)-3-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octanebenzene sulfonate;4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-1,1-diethyl-piperidiniumbenzene sulfonate;(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-trimethyl-ammoniumbenzene sulfonate;4-((S)-1-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-1-ethyl-pyridiniumbenzene sulfonate;benzyl-(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-dimethyl-ammoniumbromide;(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-ethyl-dimethyl-ammoniumbenzene sulfonate;(cis-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-trimethyl-ammoniumbenzene sulfonate;benzyl-(cis-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-dimethyl-ammoniumbromide;4-(1-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-1-methyl-ethyl)-1-methyl-pyridiniumbenzene sulfonate;(cis-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-ethyl-dimethyl-ammoniumbenzene sulfonate;1-benzyl-4-((S)-2-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionyl)-1-methyl-piperazin-1-iumbromide;4-((S)-2-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionyl)-1,1-dimethyl-piperazin-1-iumbenzene sulfonate;2-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-7,7-dimethyl-7-azonia-spiro[3.5]nonanebenzene sulfonate;4-((R)-1-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-1-methyl-pyridiniumbenzene sulfonate;(cis-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-trimethyl-ammoniumbenzene sulfonate;benzyl-(cis-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-dimethyl-ammoniumbromide;(cis-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-ethyl-dimethyl-ammoniumbenzene sulfonate;(3aR,5S,6aS)-5-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-2,2-dimethyl-octahydro-cyclopenta[c]pyrroliumbenzene sulfonate;4-((S)-2-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionylamino)-1,1-dimethyl-piperidiniumbenzene sulfonate;[4-((S)-1-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-benzyl]-trimethyl-ammoniumbenzene sulfonate;[4-((S)-1-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-benzyl]-trimethyl-ammoniumbenzene sulfonate;[5-((S)-1-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-[1,2,4]oxadiazol-3-ylmethyl]-trimethyl-ammoniumbenzene sulfonate;[2-(4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidin-1-yl)-2-oxo-ethyl]-trimethyl-ammoniumbenzene sulfonate;4-{[((S)-2-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionyl)-methyl-amino]-methyl}-1,1-dimethyl-piperidiniumbenzene sulfonate;[5-((S)-1-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-[1,3,4]oxadiazol-2-ylmethyl]-trimethyl-ammoniumbenzene sulfonate;[2-((S)-1-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-oxazol-5-ylmethyl]-trimethyl-ammoniumbenzene sulfonate;[3-(4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidin-1-yl)-3-oxo-propyl]-trimethyl-ammoniumbenzene sulfonate;9-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-3,3-dimethyl-3-azonia-spiro[5.5]undecanebenzene sulfonate;(cis-3-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclobutylmethyl)-trimethyl-ammoniumbenzene sulfonate;(trans-3-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclobutylmethyl)-trimethyl-ammoniumbenzene sulfonate;[1-((S)-2-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]-trimethyl-ammoniumbenzene sulfonate;benzyl-[1-((S)-2-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]-dimethyl-ammoniumbromide;{2-[((S)-2-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionyl)-methyl-amino]-ethyl}-trimethyl-ammoniumbenzene sulfonate;(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-dimethyl-[1,2,4]oxadiazol-3-ylmethyl-ammoniumchloride;[2-((S)-1-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-2-methyl-propyl)-oxazol-5-ylmethyl]-trimethyl-ammoniumbenzene sulfonate;[2-((S)-1-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propyl)-oxazol-5-ylmethyl]-trimethyl-ammoniumbenzene sulfonate;(4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-dimethyl-(5-methyl-isoxazol-3-ylmethyl)-ammoniumchloride;(4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexyl)-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-dimethyl-ammoniumchloride;{2-[(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexanecarbonyl)-amino]-ethyl}-trimethyl-ammoniumbenzene sulfonate[2-(1-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-1-methyl-ethyl)-oxazol-5-ylmethyl]-trimethyl-ammoniumbenzene sulfonate;[2-(1-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclopropyl)-oxazol-5-ylmethyl]-trimethyl-ammoniumbenzene sulfonate;{2-[(cis-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexanecarbonyl)-amino]ethyl}-trimethyl-ammoniumbenzene sulfonate;{2-[(cis-3-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclobutanecarbonyl)-amino]-ethyl}-trimethyl-ammoniumbenzene sulfonate;[2-(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexanecarbonyloxy)-ethyl]-trimethyl-ammoniumbenzene sulfonate;{2-[(trans-3-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclobutanecarbonyl)-amino]-ethyl}-trimethyl-ammoniumbenzene sulfonate;[2-(4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-trimethyl-ammoniumbenzene sulfonate;±[2-(1-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-ethyl)-thiazol-4-ylmethyl]-trimethyl-ammoniumbenzene sulfonate;{[(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylmethyl)-carbamoyl]-methyl}-trimethyl-ammoniumbenzene sulfonate;[(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexylcarbamoyl)-methyl]-trimethyl-ammoniumbenzene sulfonate;[1-(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexanecarbonyl)-piperidin-4-yl]-trimethyl-ammoniumbenzene sulfonate;{2-[(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexanecarbonyl)-methyl-amino]ethyl}-trimethyl-ammoniumbenzene sulfonate;4-[(trans-4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-cyclohexanecarbonyl)-amino]-1,1-dimethyl-piperidiniumbenzene sulfonate;4-[((S)-2-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-propionyl)-methyl-amino]-1,1-dimethyl-piperidiniumbenzene sulfonate;{2-[(4-[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino-piperidine-1-carbonyl)-amino]-ethyl}-trimethyl-ammonium benzenesulfonate;[2-(4-{[5-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-4-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-2,3-dihydro-imidazole-1-carbonyl]-amino}-piperidine-1-carbonyloxy)-ethyl]-trimethyl-ammoniumbenzene sulfonate;[2-(4-{[1-(4-cyano-phenyl)-5′-methyl-2′-oxo-1′-(3-trifluoromethyl-phenyl)-1′,2′-dihydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-amino}-piperidin-1-yl)-2-oxo-ethyl]-trimethyl-ammoniumbenzene sulfonate.
 10. A pharmaceutical composition, comprising acompound or salt according to claim 1 and a pharmaceutically acceptablecarrier or excipient.
 11. A pharmaceutical composition according toclaim 10 which is adapted for oral administration or administration bythe pulmonary route.
 12. A method of treatment of a disease or conditionin which HNE is implicated, comprising administering to a subject inneed thereof an effective amount of a compound or salt according toclaim
 1. 13. A method according to claim 12, wherein said disease orcondition is chronic obstructive pulmonary disease, bronchiectasis,chronic bronchitis, lung fibrosis, pneumonia, acute respiratory distresssyndrome, pulmonary emphysema, smoking-induced emphysema, or cysticfibrosis.
 14. A method according to claim 12, wherein said disease orcondition is asthma, rhinitis, psoriasis, atopic dermatitis, non-atopicdermatitis, Crohn's disease, ulcerative colitis, or irritable boweldisease.